Fused ring 4-oxopyrimidine derivative

ABSTRACT

The present invention provides a compound represented by formula (I) below, or a pharmaceutically acceptable salt thereof, which, having histamine H3 receptor antagonist or inverse agonist activity, is useful in the prophylaxis or therapy of metabolic diseases, circulatory diseases, or nervous system diseases.  
                 
 
[where, for example, Ar is a divalent group formed by eliminating two hydrogen atoms from benzene, X 1  is a nitrogen atom, sulfur atom or oxygen atom, R 1  is a 5- to 6-membered heteroaryl group, Ring A is a 5- to 6-membered heteroaryl ring, R 2  and R 3  are amino groups or alkylamino groups, and X 2  is represented by formula (II):  
                 
 
(where R 4  and R 5  are lower alkyl groups, and n is an integer from 2 to 4).]

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to fused ring 4-oxopyrimidine derivatives.

2. Related Background Art

In living creatures including mammals, histamine, an endogenous factorwith physiological activity, functions as a neurotransmitter and hasfar-reaching pharmacological effects (e.g., Life science, Vol. 17, p.503 (1975)).

From immunohistochemical research, it has become clear thathistaminergic (production) soma are present in the tubercle mammillarynuclei of the posterior hypothalmic region, and histaminergic nervefibers extend over a very large area within the brain, which suggeststhat histamine has many different pharmacological actions (e.g., Journalof Comprehensive Neurology, Vol. 273, p. 283).

The presence of a histaminergic nerve in the tubercle mammillary nucleiof the posterior hypothalamic region suggests that histamine plays aparticularly important role in cerebral function in controlling thephysiology of the hypothalmus, i.e., in waking rhythms, internalsecretions, food/water intake and sexual behavior (e.g., Progress inNeurobiology, Vol. 63, p. 637 (2001)).

The fact that there are projections of histaminergic nerve fibers toregions of the brain related to maintenance of the waking state (e.g.,the cerebral cortex) suggests that histamine has a role in maintainingthe waking state or the waking-sleep cycle. Also, the fact that thereare projections of histaminergic nerve fibers to many peripheralstructures such as the hippocampus or tonsil-like complex suggest thatit has a role in regulating the autonomic nervous system and emotions,control of motivation, learning and memory.

After histamine is released from cells producing histamine, it interactswith specific polymers called receptors on the cell membrane surface orin target cells, which account for its pharmacological effects andregulation of body functions. Four types of histamine receptors have sofar been discovered. Histamine H3 receptors have been shown by variouspharmacological and physiological studies to participate in the functionof central and peripheral nerves (e.g., Trends in PharmacologicalScience, Vol. 8, p. 24 (1986)), and in recent years, man and rodenthistamine H3 receptor genes have been identified (e.g., MolecularPharmacology, Vol. 55, p. 1101 (1999)).

It has been shown that histamine H3 receptors are present in the centeror the presynaptic membrane of peripheral nerve cells, functioning asautoreceptors, controlling the release of histamine and also controllingthe release of other neurotransmitters. Specifically, it has beenreported that histamine H3 receptor agonists, antagonists orinverse-agonists regulate the release of histamine, noradrenalin,serotonine, acetylcholine or dopamine from synaptic endings. Forexample, release of neurotransmitters such as (R)-(α)-methylhistamine issuppressed by agonists, and is promoted by antagonists orinverse-agonists like thioperamide (e.g., Trends in PharmacologicalScience, Vol. 19, p. 177 (1998)).

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide novelsubstances which have histamine H3 receptor antagonism (action ofinhibiting the binding of histamine to histamine H3 receptors) orinverse agonism (action of suppressing the constant activity ofhistamine H3 receptors), i.e. novel substances which act as histamine H3receptor antagonists or inverse-agonists.

The inventors discovered that specific fused ring 4-oxopyrimidinederivatives act as histamine H3 receptor antagonists orinverse-agonists, and on the basis of the discoveries, they arrived atthe present invention.

In order to acieve the object described above, the present inventionprovides:

(1) A compound represented by formula (I):

[where is phenyl, pyrimidinyl, pyridyl, thiazolyl, oxazolyl, pyrazolyl,thiadiazolyl or thienyl, i.e. a divalent group formed by eliminating twohydrogen atoms from benzene, pyrimidine, pyridine, thiazole, oxazole,pyrazole, thiadiazole or thiophene (this divalent group may be furthersubstituted by a halogen atom, lower alkoxy (this lower alkoxy group maybe further substituted by halogen), hydroxy or lower alkyl); X¹ is anitrogen atom, sulfur atom or oxygen atom; R¹ is a 5- or 6-memberedheteroaryl group having 1 to 4 heteroatoms selected from among nitrogen,sulfur and oxygen, heteroarylalkyl group (heteroaryl in this group hasthe same meaning as the above), straight chain or branched lower alkyl(this lower alkyl group may be further substituted by hydroxy, halogen,alkoxy, allyloxy or aralkyloxy), phenyl, aralkyl, alkoxy, alkylthio orlower alkylamino; Ring A is a 5- or 6-membered heteroaryl ring having 1or 2 nitrogen atoms or sulfur atoms in the ring, or a benzene ring; R²and R³ may be the same or different, and each represents hydrogen,amino, alkylamino, dialkylamino, nitro, cyano, hydroxy, loweralkylsulfonyl, halogen, lower alkyl (this lower alkyl group may befurther substituted by halogen), lower cycloalkyl (this lower cycloalkylgroup may be further substituted by halogen), lower alkoxy (this loweralkoxy group may be further substituted by halogen or hydroxy), lowercycloalkoxy (this lower cycloalkoxy group may be further substituted byhalogen), aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, aryl,heteroaryl, arylcarbamoyl, heteroarylcarbamoyl, arylalkylcarbamoyl,heteroarylalkylcarbamoyl, mono-lower alkylcarbamoyl, di-loweralkylcarbamoyl, lower alkylcarboxamide, arylcarboxamide,heteroarylcarboxamide, arylalkylcarboxamide, heteroarylalkylcarboxamide,alkanoyl, arylcarbonyl, arylalkylcarbonyl, formyl, hydroxy, alkylthio,alkoxycarbonylamino, lower alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, aralkyl, alkanoylamino oralkanoylalkylamino; Y is CH or a nitrogen atom; —X² is a grouprepresented by formula (II):

(where R⁴ and R⁵ may be the same or different, and each is a lower alkylgroup (this lower alkyl group may be further substituted by halogen) ora cycloalkyl group, or R⁴, R⁵ and a nitrogen atom together form a 5- to8-membered monocyclic ring (this monocyclic ring may be substituted by ahalogen atom, an oxo group, or a lower alkyl group which itself may besubstituted by halogen), or a 6- to 10-membered bicyclo ring, n is aninteger of 2 to 4, and (CH₂)_(n) may be substituted by a lower alkylgroup having 1 to 3 carbon atoms), formula (III):

(where m is an integer from 0 to 4, and R⁶ is a lower alkyl orcycloalkyl group), or formula (IV):

(where the symbols have the same meaning as the above), with the provisothat formula (I) excludes3-[4-(2-diethylaminoethoxy)-phenyl]-2-methyl-3H-quinazolin-4-one,3-[4-(2-dimethylaminoethoxy)-phenyl]-2-methyl-3H-quinazolin-4-one,2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3H-quinazolin-4-one,3-[4-(3-dimethylaminopropoxy)-phenyl]-2-methyl-3H-quinazolin-4-one,3-[4-(3-diethylaminopropoxy)-phenyl]-2-methyl-3H-quinazolin-4-one and3-[2-(2-diethylaminoethoxy)-phenyl]-2-methyl-3H-quinazolin-4-one], or apharmaceutically acceptable salt thereof;

(2) The compound according to (1), wherein Ring A is a benzene ring, apyridine ring, a pyrimidine ring or a thiophene ring, or apharmaceutically acceptable salt thereof;

(3) The compound according to (1), wherein Ring A is a benzene ring or apyridine ring, or a pharmaceutically acceptable salt thereof;

(4) The compound according to (1), (2) or (3), wherein at least one ofR² and R³ is a hydrogen atom, or a pharmaceutically acceptable saltthereof;

(5) The compound according to (1), (2) or (3), wherein one of R² and R³is a hydrogen atom, and the other is a hydrogen atom, a halogen atom,hydroxy, lower alkyl (this lower alkyl group may be further substitutedby halogen), lower alkoxy (this lower alkoxy group may be furthersubstituted by a halogen atom or hydroxy), aryl (this aryl group may befurther substituted by lower alkyl), heteroaryl, lower alkylcarboxamide,arylcarboxamide, arylalkylcarboxamide or lower alkylsulfonylamino, or apharmaceutically acceptable salt thereof;

(6) The compound according to (1), (2) or (3), wherein one of R² and R³is a hydrogen atom, and the other is a hydrogen atom, a halogen atom,lower alkyl (this lower alkyl group may be further substituted byhalogen), or lower alkoxy (this lower alkoxy group may be furthersubstituted by halogen), or a pharmaceutically acceptable salt thereof;

(7) The compound according to any one of (1) to (6), wherein Ar isphenyl or pyrimidinyl, i.e. a divalent group formed by eliminating twohydrogen atoms from benzene or pyrimidine (this divalent group may befurther substituted by a halogen atom, lower alkoxy (this lower alkoxygroup may be further substituted by halogen), hydroxy or lower alkyl),and n is 3 or 4, or a pharmaceutically acceptable salt thereof;

(8) The compound according to any one of (1) to (7), wherein —X² isrepresented by formula (II):

[where symbols have the same meaning as the above], or apharmaceutically acceptable salt-thereof;

(9) The compound according to (8), wherein n is 3 or 4, and R4, R5 and anitrogen atom together form a 5- to 8-membered monocyclic ring (thismonocyclic ring may have as a substituent group a halogen atom, or alower alkyl group which may be substituted by halogen), or apharmaceutically acceptable salt thereof;

(10) The compound according to (8), wherein n is 3 or 4, and R4, R5 anda nitrogen atom together form a 6- to 10-membered bicyclo ring, or apharmaceutically acceptable salt thereof;

(11) The compound according to (8), wherein n is 3, and R4, R5 and anitrogen atom together form a 5- to 8-membered monocyclic ring (thismonocyclic ring may have as a substituent group a halogen atom, or alower alkyl group which may be substituted by halogen), or apharmaceutically acceptable salt thereof;

(12) The compound according to (8), wherein n is 3, and R4, R5 and anitrogen atom together form a 6- to 10-membered bicyclo ring, or apharmaceutically acceptable salt thereof;

(13) The compound according to any one of (1) to (7), wherein —X² isrepresented by formula (III):

[where symbols have the same meaning as the above], or apharmaceutically acceptable salt thereof;

(14) The compound according to any one of (1) to (7), wherein —X² isrepresented by formula (IV):

[where symbols have the same meaning as the above], or apharmaceutically acceptable salt thereof;

(15) The compound according to any one of (1) to (14), wherein R¹ is alower alkyl group having 1 to 3 carbon atoms (this lower alkyl group maybe further substituted by halogen), or a phenyl group, or apharmaceutically acceptable salt thereof;

(16) The compound according to any one of (1) to (14), wherein R¹ ismethyl, ethyl, n-propyl, isopropyl or trifluoromethyl, or apharmaceutically acceptable salt thereof;

(17) The compound according to (1), wherein the compound represented byformula (I) is:

-   2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   3-{4-[3-(diethylamino)propoxy]phenyl}-2-methyl-4-(3H)-quinazolinone,-   2-methyl-3-{4-[3-(2-methyl-1-pyrrolidinyl)-propoxy]phenyl}-4(3H)-quinazolinone,-   3-{4-[3-(2,5-dimethyl-1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   2-methyl-3-{4-[4-(1-piperidinyl)butoxy]phenyl}-4(3H)-quinazolinone,-   3-{4-[3-(1-azepanyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[3-(1-azocanyl)propoxy]-phenyl}-2-methyl 4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(2-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(4-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   3-(4-{3-[(2R,6S)-2,6-dimethyl-1-piperidinyl]propoxy}phenyl)-2-methyl-4(3H)-quinazolinone,-   2-methyl-3-(4-[3-(3-methyl-1-piperidinyl)propoxy]phenyl)-4(3H)-quinazolinone,-   3-{4-[3-(3,5-dimethyl-1-piperidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   2-methyl-3-{3-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   3-{3-bromo-4-[3-(1-piperidinyl)propoxy]phenyl}-2-ethyl-4(3H)-quinazolinone,-   2-methyl-3-{4-[2-(1-piperidinyl)ethoxy]phenyl)-4(3H)-quinazolinone,-   2,5-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   3-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-propyl-4(3H)-quinazolinone,-   3-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-trifluoromethyl-4(3H)-quinazolinone,-   2-isopropyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2,6-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   7-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2,8-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-ethyl-5-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   5-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   5-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   5-hydroxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone    trifluoroacetate,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,-   7-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6,7-difluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-bromo-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6,7-dimethoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   8-chloro-2-methyl-3-[4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   8-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2,6-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-ethyl-5-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   5-fluoro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,-   5-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one,-   2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one,-   6-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,-   2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,-   2-methyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone,-   2,5-dimethyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone,-   2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[2,3-d]pyrimidin-4(3H)-one,-   6-chloro-2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,-   6-chloro-2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,-   2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,-   2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,-   2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,-   2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,-   6-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido-[3,4-d]pyrimidin-4(3H)-one,-   3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl]-4(3H)-quinazolinone,-   6-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-(hexanoylamino)-2-methyl-3-(4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-[(2-phenylacetyl)amino]2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   6-(2-naphthoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-6-[(methylsulfonyl)amino]-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-6-[(methylsulfonyl)amino]-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   7-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   7-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   7-(hexanoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   7-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   7-[(2-phenylacetyl)amino]2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   7-(2-naphthoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone-   6-[acetyl(methyl)amino]2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-6-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-6-(4-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-6-(3-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-6-(2-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(3-pyridyl)-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(4-pyridyl)-4(3H)-quinazolinone,-   2-methyl-5-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(2-pyridyl)-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-(1-cyclohexyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-(1-isopropyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-(1-ethyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-(1-butyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,-   3-{4-(1-cyclopentyl-4-piperidinyloxy)phenyl}-2,5-dimethyl-4(3H)-quinazolinone,-   7-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2,6-dimethyl-4(3H)-quinazolinone,-   6-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,-   6-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,-   5-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,-   6-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,-   6-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[3,4-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,-   2-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,-   cis-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone,-   trans-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone,-   3-{4-[(1-cyclopentyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone-   3-{4-[(1-cyclopentyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,-   3-methyl-2-{4-[3-(1-piperidinyl)propoxy]phenyl}-1(2H)-isoquinolinone,-   2-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-3-methyl-1(2H)-isoquinolinone,-   2-methyl-3-[4-{[3-(1-pyrrolidinyl)-cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone,-   2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,-   2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)    pyrido[4,3-d]pyrimidin-4(3H)-one,-   3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,-   3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,-   6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,-   6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,-   5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,-   7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,-   2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,-   5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,-   2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,-   6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,    or-   6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,    or a pharmaceutically acceptable salt thereof;

(18) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(19) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]-pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(20) The compound according to (1), wherein the compound represented byformula (I) is2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(21) The compound according to (1), wherein the compound represented byformula (I) is2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(22) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(23) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(24) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(25) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(26) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(27) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(28) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(29) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(30) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(31) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(32) The compound according to (1), wherein the compound represented byformula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(33) The compound according to (1), wherein the compound represented byformula (I) is6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(34) The compound according to (1), wherein the compound represented byformula (I) is6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(35) The compound according to (1), wherein the compound represented byformula (I) is2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(36) The compound according to (1), wherein the compound represented byformula (I) is2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(37) The compound according to (1), wherein the compound represented byformula (I) is 5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl) propoxy]phenyl}-4(3H)-quinazolinone, or a pharmaceutically acceptable saltthereof;

(38) The compound according to (1), wherein the compound represented byformula (I) is6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(39) The compound according to (1), wherein the compound represented byformula (I) is5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(40) The compound according to (1), wherein the compound represented byformula (I) is7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(41) The compound according to (1), wherein the compound represented byformula (I) is2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(42) The compound according to (1), wherein the compound represented byformula (I) is5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof;

(43) The compound according to (1), wherein the compound represented byformula (I) is2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof;

(44) The compound according to (1), wherein the compound represented byformula (I) is6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof; and

(45) The compound according to (1), wherein the compound represented byformula (I) is6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.

The compound or salt according to any one of (1) to (45) acts as ahistamine H3 receptor antagonist or inverse agonist. In other words, thepresent invention also provides a histamine H3 receptor antagonist orinverse agonist consisting of the compound according to any one of (1)to (45), or a pharmaceutically acceptable salt thereof.

According to the most recent research, histamine H3 receptors are veryactive in receptor cells and tissues, or the membrane fractions derivedfrom receptor cells and tissues, and in the living body, they areconstantly active (endogenous factors, e.g., the activity observed whenhistamine is absent) (e.g., Nature, Vol. 408, p. 860). It has beenreported that this constant activity is suppressed by inverse-agonists.For example, constant autoreceptor activity is suppressed bythioperamide or ciproxifan and, as a result, release ofneurotransmitters from synaptic endings, e.g., release and separation ofhistamine, is promoted.

In the rat, from the fact that a high-level selective inhibitor ofhistamine synthetic enzyme (histidine decarboxylase) interferes withwaking, it was shown that histamine functions to regulate motivatedwaking. In the cat, administration of (R)-(α)-methylhistamine which is ahistamine H3 receptor agonist increases deep slow wave sleep (e.g.,Brain Research, Vol. 523, p. 325 (1990)).

On the other hand, thioperamide which is a histamine H3 receptorantagonist or inverse-agonist increases wakefulness in a dose-dependentmanner. Also, thioperamide decreases slow wave and REM sleep (e.g., LifeScience, Vol. 48, p. 2397 (1991)). In addition, thioperamide or GT-2331,which is a histamine H3 antagonist or inverse agonist, decreases emotivecataplexy and sleep in the dog (e.g., Brain Research, Vol. 793, p. 279(1998)).

These findings suggest that H3 receptors participates in waking-sleepadjustment and sleep disorders, and suggest that selective histamine H3agonists, antagonists or inverse agonists may be useful for preventionor treatment of sleep disorders and conditions accompanied by sleepdisorders (e.g., idiopathic hypersomnia, recurrent hypersomnia, genuinehypersomnia, narcolepsy, periodic limb motor deficits at sleep time,sleep apnea syndrome, circadian rhythm barrier, chronic fatiguesyndrome, REM sleep disorder, sleeplessness in the elderly, lack ofsleep in night shift workers, idiopathic insomnia, repeatabilityinsomnia, inborn character insomnia, depression and integrationdysfunction syndrome).

Therefore, the compound or salt according to any one of (1) to (45)which acts as a histamine H3 receptor antagonist or inverse agonist ispresumably useful in the prophylaxis or therapy of sleep disorders, andconditions accompanied by sleep disorders.

In the rat, administration of histamine H3 antagonists, thioperamide orGT-2331, which is an inverse agonist, improves learning disability (LD)attention defecit hyperkinesia disorder (ADHD) (e.g., Life Science, Vol.69, p. 469 (2001)). In the rat, administration of(R)-(α)-methylhistamine, which is a histamine H3 receptor agonist,decreases recognition ability and learning in an object recognition testand passive obstacle test.

On the other hand, thioperamide, which is a histamine H3 antagonist orinverse agonist, improves poor memory induced by the drug scopolamine inan amnesia induction test in a dose-dependent manner (e.g.,Pharmacology, Biochemistry and Behavior, Vol. 68, p. 735 (2001)).

These findings suggest that histamine H3 receptor antagonists or inverseagonists may be useful in the prevention and therapy of memory/learningdisability and diseases accompanied by memory/learning disability, suchas Alzheimer's disease, Parkinson's disease or attentiondefect/hyperkinesia disorder.

Therefore, the compound or salt according to any one of (1) to (45) ispresumably useful in the prophylaxis or therapy of memory/learningdisability and diseases accompanied by memory/learning disability

In the rat, intraventricular administration of histamine suppressesfeeding behavior, which suggests that histamine participates in feedingbehavior adjustment (e.g., Journal of Physiology and Pharmacology Vol.49, p. 191 (1998)). Actually, thioperamide, which is a histamine H3antagonist or inverse agonist, suppresses feeding behavior in adose-dependent manner, and also promotes release of intracerebralhistamine (e.g., Behavioral Brain Research, Vol. 104, p. 147 (1999)).

These findings suggests that histamine H3 receptors participates infeeding behavior adjustment, and that histamine H3 antagonists orinverse agonists may be useful for prevention or treatment of metabolicdiseases such as eating disorder, obesity, diabetes mellitus, emaciationand hyperlipemia.

Therefore, the compound or salt according to any one of (1) to (45) ispresumably useful in the prophylaxis or therapy of such metabolicdiseases.

In the rat, administration of (R)-(α)-methylhistamine, which is ahistamine H3 receptor agonist, decreases basics diastolic pressure in adose-dependent manner. These effects are antagonized by thioperamide,which is a histamine H3 antagonist or inverse agonist (e.g., EuropeanJournal of Pharmacology, Vol. 234, p. 129 (1993)).

These findings suggest that histamine H3 receptors participate inadjustment of blood pressure, heartbeat and cardiovascular output, andthat histamine H3 receptor agonists, antagonists or inverse agonists maybe useful in prevention or therapy of circulatory diseases such ashypertension and various heart troubles.

Therefore, the compound or salt according to any one of (1) to (45) ispresumably useful in the prophylaxis or therapy of such circulatorydiseases.

In the mouse, thioperamide, which is a histamine H3 antagonist orinverse agonist, suppressed convulsion uided induced by electric shockstimuli or epileptoid strokes induced by pentylenetetrazol (PTZ) in adose-dependent manner, (e.g., European Journal of Pharmacology, Vol.234, p. 129 (1993), and Pharmacology, Biochemistry and Behavior, Vol.68, p. 735 (2001)).

These findings suggest that histamine H3 antagonists or inverse agonistsmay be useful for the prevention or treatment of epilepsy or centralconvulsions.

Therefore, the compound or salt according to any one of (1) to (45) ispresumably useful in the prophylaxis or therapy of such epilepsy orcentral convulsions.

In other words, the present invention further provides a prophylactic ortherapeutic agent for a metabolic disease, a circulatory disease or anervous system disease containing as an active ingredient the compoundaccording to any one of (1) to (45), or a pharmaceutically acceptablesalt thereof.

As the metabolic disease, there may be mentioned at least one selectedfrom the group consisting of obesity, diabetes mellitus, hormonesecretion disorders, hyperlipidemia, gout and fatty liver.

As the circulatory disease, there may be mentioned at least one selectedfrom the group consisting of angina pectoris, acute or congestive heartfailure, myocardial infarction, annular arteriosclerosis, hypertension,kidney disease and electrolyte imbalance.

As the nervous system disease, there may be mentioned at least oneselected from the group consisting of sleep disorder, diseaseaccompanied by sleep disorder, bulimia, emotional disorder, epilepsy,delirium, dementia, attention deficit/hyperactivity disorder, memoryimpairment, Alzheimer's disease, Parkinson's disease, cognitivedisorder, movement disorder, dysesthesia, dysosmia, morphine resistance,narcotics dependence, alcohol dependence and tremor.

As the nervous system disease, there may also be mentioned at least oneselected from the group consisting of idiopathic hypersomnia,repeatability hypersomnia, intrinsic hypersomnia, narcolepsy, periodiclimb movement during sleep, sleep apnea syndrome, circadian rhythmhindrance, chronic fatigue syndrome, REM sleep hindrance, sleep loss inthe elderly, night shift worker sleep insanitation, idiopathic insomnia,repeatability insomnia, intrinsic insomnia, depression, insecurity,schizophrenia.

The compound or salt according to any one of (1) to (45) may be used incombination with concomitant drugs. In other words, the presentinvention further provides a prophylactic or therapeutic agent for ametabolic disease, a circulatory disease or a nervous system diseasecontaining as active ingredients the compound according to any one of(1) to (45), or a pharmaceutically acceptable salt thereof, and aconcomitant drug. Here, examples of the concomitant drug areanti-diabetic agents, lipid lowering agents, anti-hypertensive agentsand anti-obesity agents. Two or more of these concomitant drugs may becombined.

As such prophylactic or therapeutic agent, a prophylactic or therapeuticagent for a metabolic disease, a circulatory disease or a nervous systemdisease comprising the following (i) to (iii) is further provided.

-   -   (i) the compound according to any one of (1) to (45), or a        pharmaceutically acceptable salt thereof;    -   (ii) one or more compound(s) selected from the group consisting        of the following (a) to (g):    -   (a) Histamine H3 antagonist or inverse agonist other than (i),    -   (b) a biguanide,    -   (c) a PPAR agonist,    -   (d) insulin,    -   (e) somatostatin,    -   (f) an α-glucosidase inhibitor, and    -   (g) insulin secretagogues; and    -   (iii) a pharmaceutically acceptable carrier.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The terminology used in this specification will now be described, andthen the compound relating to the present invention will be described infurther detail.

“Aryl group” means a hydrocarbon ring aryl group having 6 to 14 carbonatoms, such as phenyl, naphthyl, biphenyl or anthryl.

“Lower alkyl group” means a straight-chain or branched alkyl grouphaving 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl,isopentyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,2,2-trimethylpropyl or 1-ethyl-2-methylpropyl.

“Cycloalkyl group having 3 to 9 carbon atoms” means for examplecyclopropyl, cyclobutyl, cyclopentyl, a cyclohexyl, cycloheptyl,cyclooctyl or cyclononyl.

“Alkoxy group” means a group wherein the hydrogen atom of a hydroxygroup is substituted by the aforesaid lower alkyl group, e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy,isopentyloxy, hexyloxy or isohexyloxy.

“Alkylsulfonyl group” means a group wherein the aforesaid alkyl group iscombined with sulfonyl, e.g., methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl or butylsulfonyl.

“Alkylsulfonylamino group” means a group wherein one of the hydrogenatoms of an amino group is substituted by the aforesaid alkylsulfonylgroup, e.g., methylsulfonylamino, ethylsulfonylamino,propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino,sec-butylsulfonylamino, tert-butylsulfonylamino,N-methyl-methylsulfonylamino, N-methyl-ethylsulfonylamino,N-methyl-propylsulfonylamino, N-methyl-isopropylsulfonylamino,N-methyl-butylsulfonylamino, N-methyl-sec-butylsulfonylamino,N-methyl-tert-butylsulfonylamino, N-ethyl-methylsulfonylamino,N-ethyl-ethylsulfonylamino, N-ethyl-propylsulfonylamino,N-ethyl-isopropylsulfonylamino, N-ethyl-butylsulfonylamino,N-ethyl-sec-butylsulfonylamino or N-ethyl-tert-butylsulfonylamino.

“Cyclo lower alkylsulfonyl group” means a group wherein the aforesaid“cycloalkyl group having 3 to 9 carbon atoms” is combined with sulfonyl,e.g., cyclopropylulfonyl, cyclobutylulfonyl, cyclopentylulfonyl,cyclohexylulfonyl, cycloheptylulfonyl, cyclooctylulfonyi orcyclononylulfonyl.

“Aralkyl group” means a group wherein the aforesaid lower alkyl grouphas one of the aforesaid aryl groups, i.e., benzyl, 1-phenylethyl,2-phenylethyl, 1-naphthylmethyl or 2-naphthylmethyl.

“Heteroaryl group” means a 5- to 7-membered monocylic ring having 1 to 3hetero atoms selected from the group consisting of oxygen, sulfur andnitrogen, or a bicyclic ring wherein the monocyclic ring is fused with abenzene ring or pyridine ring, e.g., furyl, thienyl, pyrrolyl,imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyridyl, pyrimidinyl, pyridinyl, pyrazolyl, pyradinyl,quinolyl, isoquinolyl, quinazolinyl, quinolidinyl, quinoxanyl,cinnolinyl, benzoimidazolyl, imidazopyridyl, benzofuranyl,naphthylidenyl, 1,2-benzoisoxazolyl, benzoxazolyl, benzothiazolyl,oxazolopyridyl, pyridothiazolyl, isothiazolopyridyl or benzothienyl.

“Halogen atom” means fluorine, chlorine, bromine or iodine.

“Alkoxycarbonylamino group” is a group wherein one of the hydrogen atomsin an amino group is substituted by the aforesaid alkoxycarbonyl group,e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,isopropoxycarbonylamino, butoxycarbonylamino, sec-butoxycarbonylamino,tert-butoxycarbonylamino, pentyloxycarbonylamino,N-methylmethoxycarbonylamino, N-methylethoxycarbonylamino,N-methylpropoxycarbonylamino, N-methylisopropoxycarbonylamino,N-methylbutoxycarbonylamino, N-methyl-sec-butoxycarbonylamino,N-methyl-tert-butoxycarbonylamino, N-ethylmethoxycarbonylamino,N-ethylethoxycarbonylamino, N-ethylpropoxycarbonylamino,N-ethylisopropoxycarbonylamino, N-ethylbutoxycarbonylamino,N-ethyl-sec-butoxycarbonyl amino or N-ethyl-tert-butoxycarbonylamino.

“Hydroxyalkyl group” means a group wherein one of the hydrogen atoms inthe aforesaid lower alkyl group is substituted by hydroxy, e.g.,hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 1-hydroxyethyl,2-hydroxypropyl or 2-hydroxy-1-methylethyl.

“Mono-lower alkylcarbamoyl group” means a group wherein a carbamoylgroup is mono-substituted by the aforesaid lower alkyl group, e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropy carbamoyl,butylcarbamoyl, sec-butylcarbamoyl or tert-butylcarbamoyl.

“Di-lower alkylcarbamoyl group” means a carbamoyl which is disubstitutedby the same or different lower alkyl groups. Examples of “di-loweralkylcarbamoyl groups” are dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl, dipropylcarbamoyl, methylpropylcarbamoyl anddiisopropylcarbamoyl.

“Di-lower alkylcarbamoyl group” also includes a 5 to 8-memberedmonocyclic ring which the nitrogen atom forming the carbamoyl group, andthe same or different lower alkyl groups combined with the nitrogenatom, together form, or a bicyclic ring which the monocyclic ring isfused with a benzene ring or a pyridine ring to form. Specific examplesare groups represented by the following formulae.

“Alkylamino group” means a group wherein an amino group ismono-substituted by the aforesaid lower alkyl group, e.g., methylamino,ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino ortert-butylamino.

“Dialkylamino group” means a group wherein an amino group isdisubstituted by the same or different lower alkyl groups, e.g.,dimethylamino, diethylamino, dipropylamino, methylpropylamino ordiisopropylamino.

“Aminoalkyl group” means a group wherein one of the hydrogen atomsforming the aforesaid alkyl group is substituted by amino, e.g.,aminomethyl, aminoethyl or aminopropyl.

“Alkanoyl group” means a group wherein the aforesaid alkyl group iscombined with a carbonyl group, e.g., methylcarbonyl, ethylcarbonyl,propylcarbonyl or isopropylcarbonyl.

“Alkanoylamino group” means a group wherein the aforesaid alkanoyl groupis combined with an amino group, e.g., acetylamino, propanoylamino,butanoylamino, pentanoylamino, N-methylacetylamino,N-methylpropanoylamino, N-methylbutanoylamino, N-methylpentanoylamino,N-ethylacetylamino, N-ethylpropanoylamino, N-ethylbutanoylamino orN-ethylpentanoylamino.

“Mono-lower alkylaminocarbonyloxy group” means a carbonyloxy groupmono-substituted by the aforesaid lower alkyl group, e.g.,methylaminocarbonyloxy, ethylaminocarbonyloxy, propylaminocarbonyloxy orisopropylaminocarbonyloxy.

“Di-lower alkylaminocarbonyloxy group” means a carbonyloxy groupdisubstituted by the aforesaid lower alkyl groups, e.g.,dimethylaminocarbonyloxy, diethylaminocarbonyloxy,diisopropylaminocarbonyloxy or ethylmethylaminocarbonyloxy.

“Alkylthio group” means a group wherein the aforesaid alkyl group iscombined with a sulfur atom, e.g., methylthio, ethylthio, propylthio orisopropylthio.

“Cycloalkoxy group” means a group wherein the hydrogen atom of thehydroxy group is substituted by a cycloalkyl group having 3 to 9 carbonatoms, e.g., cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy orcycloheptyloxy.

“Aryloxy group” means a group wherein an oxygen atom is combined withthe aforesaid aryl group, e.g., phenoxy, naphthalen-1-yl-oxy ornaphthalen-2-yl-oxy.

“Heteroaryloxy group” means a group wherein the aforesaid heteroarylgroup is combined with an oxy group, e.g., furan-2-yl-oxy,furan-3-yl-oxy, thiophen-2-yl-oxy, thiophen-3-yl-oxy,1H-pyrrol-2-yl-oxy, 1H-pyrrol-3-yl-oxy, 1H-imidazol-2-yl-oxy,1H-imidazol-4-yl-oxy, 3H-imidazol-4-yl-oxy, 4H-[1,3,4]triazol-3-yl-oxy,2H-[1,2,4]triazol-3-yl-oxy, 1H-[1,2,4]triazol-3-yl-oxy,thiazol-2-yl-oxy, thiazol-4-yl-oxy, thiazol-5-yl-oxy, pyridin-2-yl-oxy,pyridin-3-yl-oxy, pyridin-4-yl-oxy, pyrimidin-2-yl-oxy,pyrimidin-4-yl-oxy, pyrimidin-5-yl-oxy, pyridazin-3-yl-oxy,pyridazin-4-yl-oxy, 2H-pyrazol-3-yl-oxy, 1H-pyrazol-4-yl-oxy,1H-pyrazolyl-3-oxy, pyrazin-3-yl-oxy, pyrazin-4-yl-oxy,quinolin-2-yl-oxy, quinolin-3-yl-oxy, quinolin-4-yl-oxy,isoquinolin-1-yl-oxy, isoquinolin-3-yl-oxy, isoquinolin-4-yl-oxy,quinazolin-2-yl-oxy, quinazolinyl-3-yl-oxy, quinoxalin-2-yl-oxy,quinoxalin-3-yl-oxy, cinnolin-3-yl-oxy, cinnolin-4-yl-oxy,1H-benzimidazol-2-yl-oxy, 1H-imidazo[4,5-b]pyridin-5-yl-oxy,1H-imidazo[4,5-b]pyridin-6-yl-oxy, 1H-imidazo[4,5-b]pyridin-7-yl-oxy,benzo[d]isoxazol-4-yl-oxy, benzo[d]isoxazol-5-yl-oxy,benzo[d]isoxazol-6-yl-oxy, benzoxazol-4-yl-oxy, benzoxazol-5-yl-oxy orbenzoxazol-6-yl-oxy group.

“Heteroarylalkyl group” means a group wherein the aforesaid heteroarylgroup is combined with the aforesaid alkyl group, e.g.,furan-3-yl-methyl, furan-2-yl-methyl, furan-3-yl-ethyl,furan-2-yl-ethyl, furan-3-yl-propyl, furan-2-yl-propyl,thiophen-3-yl-methyl, thiophen-2-yl-methyl, thiophen-3-yl-ethyl,thiophen-2-yl-ethyl, thiophen-3-yl-propyl, thiophen-2-yl-propyl,1H-pyrrol-3-yl-methyl, 1H-pyrrol-2-yl-methyl, 1H-pyrrol-3-yl-ethyl,1H-pyrrol-2-yl-ethyl, 1H-pyrrol-3-yl-propyl, 1H-pyrrol-2-yl-propyl,1H-imidazol-4-yl-methyl, 1H-imidazol-2-yl-methyl,1H-imidazol-5-yl-methyl, 1H-imidazol-4-yl-ethyl, 1H-imidazol-2-yl-ethyl,1H-imidazol-5-yl-ethyl, 1H-imidazol-4-yl-propyl,1H-imidazol-2-yl-propyl, 1H-imidazol-5-yl-propyl,1H-[1,2,3]triazol-4-yl-methyl, 1H-[1,2,3]triazol-5-yl-methyl,1H-[1,2,3]triazol-4-yl-ethyl, 1H-[1,2,3]triazol-5-yl-ethyl,1H-[1,2,3]triazol-4-yl-propyl, 1H-[1,2,3]triazol-5-yl-propyl,1H-[1,2,4]triazol-3-yl-methyl, 1H-[1,2,4]triazol-5-yl-methyl,1H-[1,2,4]triazol-3-yl-ethyl, 1H-[1,2,4]triazol-5-yl-ethyl,1H-[1,2,4]triazol-3-yl-propyl, 1H-[1,2,4]triazol-5-yl-propyl,thiazol-4-yl-methyl, thiazole-3-yl-methyl, thiazol-2-yl-methyl,thiazol-4-yl-ethyl, thiazol-3-yl-ethyl, thiazol-2-yl-ethyl,thiazol-4-yl-propyl, thiazol-3-yl-propyl, thiazol-2-yl-propyl,[1,2,4]thiadiazol-3-yl-methyl, [1,2,4]thiadiazol-3-yl-ethyl,[1,2,4]thiadiazol-3-yl-propyl, [1,2,4]thiadiazol-5-yl-methyl,[1,2,4]thiadiazol-5-yl-ethyl, [1,2,4]thiadiazol-5-yl-propyl,[1,3,4]thiadiazol-2-yl-methyl, [1,3,4]thiadiazol-2-yl-ethyl or[1,3,4]thiadiazol-2-yl-propyl.

“Monoarylcarbamoyl group” means a carbamoyl group mono-substituted bythe aforesaid aryl group, e.g., phenylcarbamoyl.

Next, the compound represented by the aforesaid formula (I) relating tothe present invention will be described in further detail.

The symbols used in formula (I) will first be described.

[where the symbols have the same meaning as the above.]

Ar is phenyl, pyrimidinyl, pyridyl, thiazolyl, oxazolyl, pyrazolyl,thiadiazolyl or thienyl, i.e. a divalent group formed by eliminating twohydrogen atoms from benzene, pyrimidine, pyridine, thiazole, oxazole,pyrazole, thiadiazole or thiophene, but among these, phenyl orpyrimidinyl, i.e a divalent group formed by eliminating two hydrogenatoms from benzene or pyrimidine, is preferred.

Ar may be substituted by halogen, lower alkoxy, hydroxy and lower alkyl.Examples of this halogen are fluorine, bromine and chlorine. As thelower alkoxy there may be mentioned methoxy and ethoxy. This loweralkoxy group may be further substituted by halogen. As the lower alkylthere may be mentioned methyl and ethyl.

X¹ is a nitrogen atom, a sulfur atom or an oxygen atom, but among these,an oxygen atom is preferred.

X² is represented by formula (II):

[where the symbols have the same meaning as the above], formula (III):

[where the symbols have the same meaning as the above], or formula (IV):

[where the symbols have the same meaning as the above].

The case where —X² is represented by formula (II) will first bedescribed.

[where the symbols have the same meaning as the above.]

n is an integer from 2 to 4, preferably 3 or 4, but more preferably 3.

The “lower alkyl groups” represented by R⁴ and R⁵ are identical to theabove. More specifically, this lower alkyl group may for example bemethyl, ethyl, propyl or isopropyl.

The “lower alkyl groups” represented by R⁴ and R⁵ may be the same ordifferent.

The “cycloalkyl groups” represented by R⁴ and R⁵ are identical to theabove. This cycloalkyl group may for example be cyclopropyl, cyclobutylor the like.

R⁴, R⁵ and a nitrogen atom in the aforesaid formula (II) may form a 5-to 8-membered monocyclic ring (in addition to the nitrogen atomadjoining R⁴ and R⁵, this ring may further have a hetero atom selectedfrom among a nitrogen atom, a sulfur atom and an oxygen atom) Examplesof this 5- to 8-membered monocyclic ring are a pyrrolidine ring, apiperidine ring, a homopiperidine ring, a heptamethyleneimine ring, apiperazine ring, a morpholine ring and a homomorpholine ring.

R⁴, R⁵ and the nitrogen atom in the aforesaid formula (II) may also forma bicyclo ring. This bicyclo ring is an aza-bicyclic ring, and is anon-aromatic ring containing the nitrogen atom adjoining R⁴ and R⁵ inthe aforesaid formula (II) as the only hetero atom forming the ring.This ring preferably has 6 to −10 ring-forming atoms, but morepreferably 7 to 9 ring-forming atoms.

Examples of this bicyclo ring are groups represented by formulae (V).

(CH₂)_(n) in the aforesaid formula (II) may be substituted by a loweralkyl group having 1 to 3 carbon atoms. Examples of this lower alkylgroup are methyl, ethyl, n-propyl and isopropyl.

When X² is a group represented by the aforesaid formula (II), it ispreferred that n is 3 or 4, and R4, R5 and a nitrogen atom together forma 5- to 8-membered monocyclic ring (this monocyclic ring may have as asubstituent group a halogen atom, or a lower alkyl group which may besubstituted by halogen), or form a 6- to 10-membered bicyclo ring, andmore preferred that n is 3, and R4, R5 and a nitrogen atom together forma 5- to 8-membered monocyclic ring (this monocyclic ring may have as asubstituent group a halogen atom, or a lower alkyl group which may besubstituted by halogen), or form a 6- to 10-membered bicyclo ring.

The case where —X² is represented by formula (III) will now bedescribed.

[where the symbols have the same meaning as the above.]

m is an integer from 0 to 4, among which, 2 or 3 is preferred.

R⁶ is a lower alkyl group or a cycloalkyl group.

The “lower alkyl group” represented by R⁶ is identical to the above.More specifically, this lower alkyl group may for example be alkyl,methyl, ethyl, propyl, butyl or pentyl.

The “cycloalkyl group” represented by R⁶ is identical to the aforesaidlower alkyl group, for example, methyl, ethyl, propyl, butyl, isopropyl,isobutyl, tert-butylpentyl, isoamyl, neopentyl, 1,1-dimethylpropyl,1-methylbutyl, 2-methylbutyl, hexyl, isohexyl, 1-methylpentyl or1,1-dimethylbutyl.

When —X² is represented by formula (III), two different carbon atoms ofthe carbon atoms forming X² may be joined together via —(CH₂)m11- (m11is an integer from 1 to 3) to form a bicyclo ring. Examples of thisbicyclo ring are groups represented by formulae (III-2)

[where the symbols have the same meaning as the above.]

The case where —X² is represented by formula (IV) will now be described.

[where the symbols have the same meaning as the above.]

m is an integer from 0 to 4, among which, 2 or 3 is preferred.

R⁴ and R⁵ have the same meanings as the above, and the preferred andmore preferred aspects are identical to the aforesaid aspects of R⁴ andR⁵.

When —X² is represented by formula (IV), two different carbon atoms ofthe carbon atoms forming X² (except the carbon atoms in R⁴ and R⁵) maybe joined together via a single bond or —(CH₂)m11- (m11 is an integerfrom 1 to 3) to form a bicyclo ring. Examples of this bicyclo ring aregroups represented by formulae (IV-2)

[where the symbols have the same meaning as the above.]

When —X² is one of the bicyclo rings represented by formulae (IV-2), thepreferred aspects of R⁴ and R⁵ are identical to the above.

From the above, more specifically, X² may for example be2-dimethylaminoethyl, 2-diethylaminoethyl, 2-di-n-propylaminoethyl,2-diisopropylaminoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl,3-di-n-propylaminopropyl, 3-diisopropylaminopropyl,4-dimethylaminobutyl, 4-diethylaminobutyl, 4-di-n-propylaminobutyl,4-diisopropylaminobutyl, 2-(ethylmethylamino)ethyl,2-(ethylpropylamino)ethyl, 2-(ethylisopropylamino)ethyl,2-(methylisopropylamino)ethyl, 2-(ethyl-n-propylamino)ethyl,3-(ethylmethylamino)propyl, 3-(ethylpropylamino)propyl,3-(ethylisopropylamino)propyl, 3-(methylisopropylamino)propyl,2-(ethyl-n-propylamino)propyl, 4-(ethylmethylamino)butyl,4-(ethylpropylamino)butyl, 4-(ethylisopropylamino)butyl,2-(ethyl-n-propylamino)butyl, 2-dicyclopropylaminoethyl,2-dicyclobutylaminoethyl, 2-dicyclopentylaminoethyl,2-dicyclohexylaminoethyl, 3-dicyclopropylaminopropyl,3-dicyclobutylaminopropyl, 3-dicyclopentylaminopropyl,3-dicyclohexylaminopropyl, 4-dicyclopropylaminobutyl,4-dicyclobutylaminobutyl, 4-dicyclopentylaminobutyl,4-dicyclohexylaminobutyl, 2-(cyclobutyl-cyclopropylamino)ethyl,2-(cyclobutyl-cyclopentylamino)ethyl, 2-(cyclohexyl-cyclopentyl)ethyl,3-(cyclobutyl-cyclopropylamino)propyl,3-(cyclobutyl-cyclopentylamino)propyl,3-(cyclohexyl-cyclopentylamino)propyl,4-(cyclobutyl)-cyclopropylaminobutyl,4-(cyclobutyl-cyclopentylamino)butyl,4-(cyclohexyl-cyclopentylamino)butyl, 2-(cyclopropylmethylamino)ethyl,2-(cyclopropylethylamino)ethyl, 2-(cyclopropyl-n-propylamino)ethyl,2-(cyclopropylisopropylamino)ethyl, 2-(cyclobutylmethylamino)ethyl,2-(cyclobutylethylamino)ethyl, 2-(cyclobutyl-n-propylamino)ethyl,2-(cyclobutylisopropylamino)ethyl, 2-(cyclopentylmethylamino)ethyl,2-(cyclopentylethylamino)ethyl, 2-(cyclopentyl-n-propylamino ethyl,2-(cyclopentylisopropylamino)ethyl, 2-(cyclohexylmethylamino)ethyl,2-(cyclohexylethylamino)ethyl, 2-(cyclohexyl-n-propyl)aminoethyl,2-(cyclohexylisopropylamino)ethyl, 3-(cyclopropylmethylamino)propyl,3-(cyclopropylethylamino)propyl, 3-(cyclopropyl-n-propylamino)propyl,3-(cyclopropylisopropylamino)propyl, 3-(cyclobutylmethylamino)propyl,3-(cyclobutylethylamino)propyl, 3-(cyclobutyl-n-propylamino)propyl,3-(cyclobutylisopropylamino)propyl, 3-(cyclopentylmethylamino)propyl,3-(cyclopentyl)-ethylaminopropyl, 3-(cyclopentyl-n-propylamino) propyl,3-(cyclopentylisopropylamino)propyl, 3-(cyclohexylmethylamino)propyl,3-(cyclohexylethylamino)propyl, 3-(cyclohexyl-n-propylamino)propyl,3-(cyclohexylisopropylamino)propyl, 4-(cyclopropylmethylamino)butyl,4-(cyclopropylethylamino)butyl, 4-(cyclopropyl-n-propylamino)butyl,4-(cyclopropylisopropylamino)butyl, 4-(cyclobutylmethylamino)butyl,4-(cyclobutylethylamino)butyl, 4-(cyclobutyl-n-propylamino)butyl,4-(cyclobutylisopropylamino)butyl, 4-(cyclopentylmethylamino)butyl,4-(cyclopentylethylamino)butyl, 4-(cyclopentyl-n-propylamino)butyl,4-(cyclopentylisopropylamino) butyl, 4-(cyclohexylmethylamino)butyl,4-(cyclohexylethylamino)butyl, 4-(cyclohexyl-n-propylamino)butyl,4-(cyclohexylisopropylamino)butyl, 2-pyrrolidin-1-yl-ethyl,2-piperidin-1-yl-ethyl, 2-homopiperidin-1-yl-ethyl,2-hepta-methyleneimin-1-yl-ethyl, 2-morpholin-4-yl-ethyl,2-homomorpholin-4-yl-ethyl, 3-pyrrolidin-1-yl-propyl,3-piperidin-1-yl-propyl, 3-homopiperidin-1-yl-propyl,3-hepta-methyleneimin-1-yl-propyl, 3-morpholin-4-yl-propyl,3-homomorpholin-4-yl-propyl, 4-pyrrolidin-1-yl-butyl,4-piperidin-1-yl-butyl, 4-homopiperidin-1-yl-butyl,4-hepta-methyleneimin-1-yl-butyl, 4-morpholin-4-yl-butyl,4-homomorpholin-4-yl-butyl, 2-(5-aza-bicyclo[2.1.1]hexan-5-yl-ethyl,2-(6-aza)-bicyclo[3.1.1]heptan-6-yl-ethyl,2-(7-aza-bicyclo[2.1.1]heptan-7-yl-ethyl),2-(8-aza-bicyclo[3.2.1]octan-8-yl-ethyl),2-(9-aza-bicyclo[3.3.1]nonan-9-yl-ethyl),3-(5-aza-bicyclo[2.1.1]hexan-5-yl-propyl),3-(6-aza-bicyclo[3.1.1]heptan-6-yl-propyl),3-(7-aza-bicyclo[2.1.1]heptan-7-yl-propyl),3-(8-aza-bicyclo[3.2.1]octan-8-yl-propyl),3-(9-aza-bicyclo[3.3.1]nonan-9-yl-propyl),4-(5-aza-bicyclo[2.1.1]hexan-5-yl-butyl),4-(6-aza-bicyclo[3.1.1]heptan-6-yl-butyl),4-(7-aza-bicyclo[2.1.1]heptan-7-yl-butyl),4-(8-aza-bicyclo[3.2.1]octan-8-yl-butyl,4-(9-aza-bicyclo[3.3.1]nonan-9-yl-butyl, 1-methylazetidin-3-yl,1-methyl-azetidin-2-yl), 1-ethylazetidin-3-yl, 1-ethyl-azetidin-2-yl,1-isopropylazetidin-3-yl, 1-isopropylazetidin-2-yl,1-cyclopropylazetidin-3-yl, 1-cyclobutylazetidin-2-yl,1-cyclobutylazetidin-3-yl, 1-cyclobutylazetidin-2-yl,1-cyclopentylazetidin-3-yl, 1-cyclopentylazetidin-2-yl,1-cyclohexylazetidin-3-yl, 1-cyclohexylazetidin-2-yl,1-methylpyrrolidin-3-yl, 1-methylpyrrolidin-2-yl,1-ethylpyrrolidin-3-yl, 1-ethylpyrrolidin-3-yl,1-isopropylpyrrolidin-3-yl, 1-isopropylpyrrolidin-2-yl,1-cyclopropylpyrrolidin-3-yl, 1-cyclopropylpyrrolidin-2-yl,1-cyclobutylpyrrolidin-3-yl, 1-cyclobutylpyrrolidin-2-yl,1-cyclopentylpyrrolidin-3-yl, 1-cyclopentylpyrrolidin-2-yl,1-cyclohexylpyrrolidin-3-yl, 1-cyclohexylpyrrolidin-2-yl,1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-2-yl,1-ethylpiperidin-4-yl, 1-ethylpiperidin-3-yl, 1-ethylpiperidin-2-yl,1-isopropylpiperidin-4-yl, 1-isopropylpiperidin-3-yl,1-isopropylpiperidin-2-yl, 1-cyclopropylpiperidin-4-yl,1-cyclopropylpiperidin-3-yl, 1-cyclopropylpiperidin-2-yl,1-cyclobutylpiperidin-4-yl, 1-cyclobutylpiperidyl-3-yl,1-cyclobutylpiperidin-2-yl, 1-cyclopentylpiperidin-4-yl,1-cyclopentylpiperidin-3-yl, 1-cyclopentylpiperidin-2-yl,1-cyclohexylpiperidin-4-yl, 1-cyclohexylpiperidin-3-yl,1-cyclohexylpiperidin-2-yl, 3-dimethylaminocyclobutyl,3-diethylaminocyclobutyl, 3-diisopropylaminocyclobutyl,3-dicyclopropylaminobutyl, 3-dicyclobutylaminobutyl,3-dicyclopentylaminobutyl, 3-dicyclohexylaminobutyl,2-dimethylaminocyclobutyl, 2-diethylaminocyclobutyl,2-diisopropylaminocyclobutyl, 2-dicyclopropylaminobutyl,2-dicyclobutylaminobutyl, 2-dicyclopentylaminobutyl,2-dicyclohexylaminobutyl, 3-(cyclopropylmethylamino)cyclobutyl,3-(cyclopropylethylamino)cyclobutyl,3-(cyclobutylmethylamino)cyclobutyl, 3-(cyclobutylethylamino)cyclobutyl,3-(cyclopentylmethylamino)cyclobutyl,3-(cyclopentylethylamino)cyclobutyl,3-(cyclohexylmethylamino)cyclobutyl,2-(cyclopropylmethylamino)cyclobutyl,2-(cyclopropylethylamino)cyclobutyl,2-(cyclobutylmethylamino)cyclobutyl, 2-(cyclobutylethylamino)cyclobutyl,2-(cyclopentylmethylamino)cyclobutyl,2-(cyclopentylethylamino)cyclobutyl,2-(cyclohexylmethylamino)cyclobutyl, 3-pyrrolidin-1-yl-cyclobutyl,2-pyrrolidin-1-yl-cyclobutyl, 3-pyrrolidin-1-yl-cyclopentyl,2-pyrrolidin-1-yl-cyclopentyl, 4-pyrrolidin-1-yl-cyclohexyl,3-pyrrolidin-1-yl-cyclohexyl, 2-pyrrolidin-1-yl-cyclohexyl,3-piperidin-1-yl-cyclobutyl, 2-piperidin-1-yl-cyclobutyl,3-piperidin-1-yl-cyclopentyl, 2-piperidin-1-yl-cyclopentyl,4-piperidin-1-yl-cyclohexyl, 3-piperidin-1-yl-cyclohexyl,2-piperidin-1-yl-cyclohexyl, 3-homopiperidin-1-yl-cyclobutyl,2-homopiperidin-1-yl-cyclobutyl, 3-homopiperidin-1-yl-cyclopentyl,2-homopiperidin-1-yl-cyclopentyl, 4-homopiperidin-1-yl-cyclohexyl,3-homopiperidin-1-yl-cyclohexyl, 2-homopiperidin-1-yl-cyclohexyl,3-hepta-methyleneimin-1-yl-cyclobutyl,2-hepta-methyleneimin-1-yl-cyclobutyl,3-hepta-methyleneimin-1-yl-cyclopentyl,2-hepta-methyleneimin-1-yl-cyclopentyl,4-hepta-methyleneimin-1-yl-cyclohexyl,3-hepta-methyleneimin-1-yl-cyclohexyl,2-hepta-methyleneimin-1-yl-cyclohexyl, 2-morpholin-4-yl-cyclobutyl,3-morpholin-4-yl-cyclobutyl, 2-morpholin-4-yl-cyclopentyl,3-morpholin-4-yl-cyclopentyl, 2-morpholin-4-yl-cyclohexyl,3-morpholin-4-yl-cyclohexyl, 4-morpholin-4-yl-cyclohexyl,2-homomorpholin-4-yl-cyclobutyl, 3-homomorpholin-4-yl-cyclobutyl,4-homomorpholin-4-yl-cyclobutyl, 2-homomorpholin-4-yl-cyclopentyl,3-homomorpholin-4-yl-cyclopentyl, 4-homomorpholin-4-yl-cyclopentyl,2-homomorpholin-4-yl-cyclohexyl, 3-homomorpholin-4-yl-cyclohexyl,4-homomorpholin-4-yl-cyclohexyl,2-(5-aza-bicyclo[2.1.1]hexan-5-yl)cyclobutyl,2-(6-aza-bicyclo[3.1.1]heptan-6-yl)cyclobutyl,2-(7-aza-bicyclo[2.1.1]heptan-7-yl)cyclobutyl,2-(8-aza-bicyclo[3.2.1]octan-8-yl)cyclobutyl,2-(9-aza-bicyclo[3.3.1]nonan-9-yl)cyclobutyl,3-(5-aza-bicyclo[2.1.1]hexan-5-yl)cyclobutyl,3-(6-aza-bicyclo[3.1.1]heptan-6-yl)cyclobutyl,3-(7-aza-bicyclo[2.1.1]heptane)-7-yl-cyclobutyl,3-(8-aza-bicyclo[3.2.1]octan-8-yl)cyclobutyl,3-(9-aza-bicyclo[3.3.1]nonan-9-yl)cyclobutyl,2-(5-aza-bicyclo[2.1.1]hexan-5-yl)cyclopentyl,2-(6-aza-bicyclo[3.1.1]heptan-6-yl)cyclopentyl,2-(7-aza-bicyclo[2.1.1]heptan-7-yl)cyclopentyl,2-(8-aza-bicyclo[3.2.1]octan-8-yl)cyclopentyl,2-(9-aza-bicyclo[3.3.1]nonan-9-yl)cyclopentyl,3-(5-aza-bicyclo[2.1.1]hexan-5-yl)cyclopentyl,3-(6-aza)-bicyclo[3.1.1]heptan-6-yl-cyclopentyl,3-(7-aza-bicyclo[2.1.1]heptan-7-yl)cyclopentyl,3-(8-aza-bicyclo[3.2.1]octan-8-yl)cyclopentyl,3-(9-aza-bicyclo[3.3.1]nonan-9-yl)cyclopentyl,2-(5-aza-bicyclo[2.1.1]hexan-5-yl)cyclohexyl,2-(6-aza-bicyclo[3.1.1]heptan-6-yl)cyclohexyl,2-(7-aza-bicyclo[2.1.1]heptan-7-yl)cyclohexyl,2-(8-aza-bicyclo[3.2.1]octan-8-yl)cyclohexyl,2-(9-aza-bicyclo[3.3.1]nonan-9)-yl-cyclohexyl,3-(5-aza-bicyclo[2.1.1]hexan-5-yl)cyclohexyl,3-(6-aza-bicyclo[3.1.1]heptan-6-yl)cyclohexyl,3-(7-aza-bicyclo[2.1.1]heptan-7-yl)cyclohexyl,3-(8-aza-bicyclo[3.2.1]octan-8-yl)cyclohexyl,3-(9-aza-bicyclo[3.3.1]nonan-9-yl)cyclohexyl,3-(7-aza-bicyclo[2.2.1]hepto-7-yl)propyl,3-(8-aza-bicyclo[3.2.1]octo-8-yl)propyl,3-(3,3-difluoropyrrolidin-1-yl)propyl, 3-(3-fluoropiperidin-1-yl)propyl,3-[(3R)-3-fluoropyrrolidin-1-yl]propyl,3-(4,4-difluoropiperidin-1-yl)propyl, 3-(4-fluoropiperidin-1-yl)propyl,3-(3,3-difluoropiperidin-1-yl)propyl,3-[(3R)-3-methylpiperidin-1-yl]propyl,3-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]propyl,3-[3-methylpyrrolidin-1-yl-propyl,3-[(2S)-2-methylpyrrolidin-1-yl]propyl,3-[(2R)-2-methylpyrrolidin-1-yl]propyl,3-[(3S)-3-methylpiperidin-1-yl]propyl, 3-(azepan-1-yl)propyl,3-[(2-oxopyrrolidin-1-yl)]propyl. Among these, 3-piperidin-1-yl-propyl,1-cyclobutylpiperidin-4-yl, 1-cyclopentylpiperidin-4-yl,3-[(3S)-3-methylpiperidin-1-yl]propyl,3-[(2R)-2-methylpyrrolidin-1-yl]propyl,3-[(2S)-2-methylpyrrolidin-1-yl]propyl, 1-cyclopentylpiperidin-4-yl,3-(pyrrolidin-1-yl)propyl, 3-(piperidin-1-yl)propyl are preferred.

R¹ is a 5- to 6-membered heteroaryl group having 1 to 4 hetero atomsselected from among nitrogen, sulfur and oxygen in the ring, aheteroarylalkyl group, a straight-chain or branched lower alkyl group(this lower alkyl group may further be substituted by hydroxy, halogen,alkoxy, allyloxy or aralkyloxy), a phenyl group, an aralkyl group, analkoxy group, an alkylthio group or a lower alkylamino group.

In the “5- to 6-membered heteroaryl group having 1 to 4 hetero atomsselected from among nitrogen, sulfur and oxygen in the ring” representedby R¹, when the ring contains 2 to 4 heteroatoms, these hetero atoms maybe the same or different. Examples of 5- to 6-membered heteroaryl groupsare furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl,thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl,pyridinyl, pyrazolyl and pyradinyl.

The “heteroarylalkyl group” represented by R¹ has the same meaning asthe above.

R¹ is preferably a lower alkyl group having 1 to 3 carbon atoms (thislower alkyl group may be further substituted by halogen), or phenyl, butmore prefarably, methyl, ethyl, n-propyl, isopropyl or trifluoromethyl.

R² and R³ may be the same or different, and each represents a hydrogenatom, amino, nitro, cyano, hydroxy, lower alkylsulfonyl, a halogen atom,lower alkyl (this lower alkyl group may be further substituted byhydroxy or a halogen atom), lower cycloalkyl (this lower cycloalkylgroup may be further substituted by a halogen atom), lower alkoxy (thislower alkoxy group may be further substituted by a halogen atom), lowercycloalkoxy (this lower cycloalkoxy group may be further substituted bya halogen atom), aryloxy, aralkyloxy, aryl, heteroaryl, mono-loweralkylcarbamoyl, di-lower alkylcarbamoyl, lower alkylcarboxamide,arylcarboxamide, heteroarylcarboxamide, alkanoyl, alkylthio,alkoxycarbonylamino, alkyl, arylsulfonylamino, alkylaminosulfonyl,arylaminosulfonyl, aralkyl, alkanoylamino or alkanoylalkylamino.

The “lower alkylsulfonyl group” represented by R² or R³ has the samemeaning as the above.

The “lower alkyl group” represented by R² or R³ has the same meaning asthe above. This lower alkyl group may be further substituted by ahydroxy group, or a halogen atom such as chlorine or fluorine.

The “lower alkoxy group” represented by R² or R³ has the same meaning asthe above.

The “cyclo lower alkoxy group” represented by R² or R³ means a groupwherein the aforesaid cyclo lower alkyl group is combined with an oxygenatom. This cyclo lower alkoxy group may be further substituted by ahalogen atom such as chlorine or fluorine.

The “aryloxy group” represented by R² or R³ has the same meaning as theabove.

The “aralkyloxy group” represented by R² or R³ means a group wherein theaforesaid aralkyl group is combined with an oxygen atom.

The “aryl group” represented by R² or R³ has the same meaning as theabove.

The “heteroaryl group” represented by R² or R³ has the same meaning asthe above.

The “mono-lower alkylcarbamoyl group” represented by R² or R³ has thesame meaning as the above.

The “di-lower alkylcarbamoyl group” represented by R² or R³ has the samemeaning as the above.

The “lower alkylcarboxamide group” represented by R² or R³ means a groupwherein the aforesaid branched or straight-chain alkyl group having 1 to6 carbon atoms is combined with carboxamide, e.g., methylcarboxamide,ethyl carboxamide or isopropylcarboxamide.

The “alkanoyl group” represented by R² or R³ means a group wherein theaforesaid alkyl group is combined with carbonyl, e.g., methylcarbonyl,ethylcarbonyl, propylcarbonyl or isopropylcarbonyl.

The “alkylthio group” represented by R² or R³ means a group wherein theaforesaid alkyl group is combined with sulfur, e.g., methylthio,ethylthio, propylthio or isopropylthio.

The “alkoxycarboxamide group” represented by R² or R³ means a groupwherein the aforesaid alkoxy group is combined with carboxamide, e.g.,methoxycarboxamide, ethoxycarboxamide or isopropoxycarboxamide.

The “arylcarboxamid group” represented by R² or R³ means a group whereinthe aforesaid aryl group is combined with carboxamide, e.g.,phenylcarboxamide or naphthylcarboxamide.

The “heteroarylcarboxamide group” represented by R2 or R³ means a groupwherein the aforesaid heteroaryl group is combined with carboxamide,e.g., furylcarboxamide, thienylcarboxamide or pyrrolylcarboxamide.

The “arylsulfonylamino group” represented by R² or R³ means a groupwherein the aforesaid aryl group is combined with sulfonylamino, e.g.,phenylsulfonylamino or naphthylsulfonylamino.

The “alkylaminosulfonyl group” represented by R² or R³ means a groupwherein the aforesaid alkyl group is combined with aminosulfonyl, e.g.,methylaminosulfonyl, ethylaminosulfonyl or isopropylaminosulfonyl.

The “arylaminosulfonyl group” represented by R² or R³ means a groupwherein the aforesaid aryl group is combined with aminosulfonyl, e.g.,phenylaminosulfonylamino or naphthylaminosulfonylamino.

The “aralkyl group” represented by R² or R³ has the same meaning as theabove.

The “alkanoylalkylamino group” represented by R² or R³ means a groupwherein the aforesaid alkanoyl group is combined with the aforesaidalkylamino, e.g., acetylmethylamino or acetylethylamino.

Ring A is a 5- to 6-membered heteroaryl ring having 1 or 2 hetero atomsselected from among nitrogen or sulfur in the ring, or a benzene ring.This Ring A may for example be a benzene ring, thiophene ring, pyridinering, pyrimidine ring or pyrazine ring, among which, a benzene ring,pyridine ring and pyrimidine ring are preferred, and a benzene ring andpyridine ring are more preferred.

When the 5- to 6-membered heteroaryl ring represented by Ring A has twohetero atoms, the hetero atoms may be the same or different.

The aforesaid substituent groups R² or R³ on this Ring A may be the sameor different.

From the above, groups represented by formula (VI):

[where the symbols have the same meaning as the above, and formula(VI-0):

shows the bonding site] may for example be groups represented byformulae (VI-1):

[where the symbols have the same meaning as the above], among which,groups represented by formulae (VI-2):

[where the symbols have the same meaning as the above] are preferred,and among these, groups represented by formulae (VI-3):

[where the symbols have the same meaning as the above] are morepreferred.

Any of the preferred aspects of Ar, X¹, X², Y, R¹ R², R³, R⁴, R⁵, R⁶, n,m and Ring A, which are described above, may be combined.

More specifically, the compound represented by formula (I):

[where the symbols have the same meaning as the above] are preferably2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(diethylamino)propoxy]phenyl}-2-methyl-4-(3H)-quinazolinone,2-methyl-3-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(2,5-dimethyl-1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,2-methyl-3-{4-[4-(1-piperidinyl)butoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(1-azepanyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[3-(1-azocanyl)propoxy]phenyl}-2-methyl 4(3H)-quinazolinone,2-methyl-3-{4-[3-(2-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(4-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-(4-{3-[(2R,6S)-2,6-dimethyl-1-piperidinyl]propoxy}phenyl)-2-methyl-4(3H)-quinazolinone,2-methyl-3-{4-[3-(3-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(3,5-dimethyl-1-piperidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,2-methyl-3-{3-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{3-bromo-4-[3-(1-piperidinyl)propoxy]phenyl}-2-ethyl-4(3H)-quinazolinone,2-methyl-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-4(3H)-quinazolinone,2,5-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-propyl-4(3H)-quinazolinone,3-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-trifluoromethyl-4(3H)-quinazolinone,2-isopropyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2,6-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2,8-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl]-4(3H)-quinazolinone,2-ethyl-5-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-hydroxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonetrifluoroacetate,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,7-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6,7-difluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-bromo-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6,7-dimethoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,8-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,8-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2,6-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-ethyl-5-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one,6-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one,2-methyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone,2,5-dimethyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone,2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one,6-chloro-2-ethyl-3-[4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-chloro-2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one,6-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[3-(1-piperidinyl)propoxy]phenyl]-4(3H)-quinazolinone,6-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(hexanoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-[(2-phenylacetyl)amino]-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(2-naphthoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-[(methylsulfonyl)amino]-3-{3-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-[(methylsulfonyl)amino]-3-{3-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(hexanoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-[(2-phenylacetyl)amino]-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(2-naphthoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-[acetyl-(methyl)amino]-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-(4-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-(3-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-(2-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(3-pyridyl)-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(4-pyridyl)-4(3H)-quinazolinone,2-methyl-5-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(2-pyridyl)-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-cyclohexyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-isopropyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-ethyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-butyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,3-{4-(1-cyclopentyl-4-piperidinyloxy)phenyl}-2,5-dimethyl-4(3H)-quinazolinone,7-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2,6-dimethyl-4(3H)-quinazolinone,6-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,6-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,5-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]pyrimidin-4(3H)-one,6-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,6-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyriddo[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[3,4-d]pyrimidin-4(3H)-one,2-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,cis-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone,trans-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-methyl-2-{4-[3-(1-piperidinyl)propoxy]phenyl}-1(2H)-isoquinoline,2-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-3-methyl-1(2H)-isoquinoline, or2-methyl-3-[4-{[3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone.

As the compound (I) relating to the present invention functions as ahistamine H3 receptor antagonist or inverse agonist, it is useful as aprophylactic or therapeutic agent for metabolic diseases such asobesity, diabetes mellitus, hormone secretion disorders, hyperlipidemia,gout and fatty liver; circulatory diseases such as angina pectoris,acute or congestive heart failure, myocardial infarction, annulararteriosclerosis, hypertension, kidney disease and electrolyteimbalance; and/or central or peripheral nervous system diseases such assleep disorders or diseases accompanied by sleep disorders (e.g.,idiopathic hypersomnia, repeatability hypersomnia, intrinsichypersomnia, narcolepsy, periodic limb movement during sleep, sleepapnea syndrome, circadian rhythm hindrance, chronic fatigue syndrome,REM sleep hindrance, sleep loss in the elderly, night shift worker sleepinsanitation, idiopathic insomnia, repeatability insomnia, intrinsicinsomnia, depression, insecurity and schizophrenia), bulimia, emotionaldisorders, epilepsy, delirium, dementia, attention deficit/hyperactivitydisorder, memory impairment, Alzheimer's disease, Parkinson's disease,cognitive disorder, movement disorder, dysesthesia, dysosmia, morphineresistance, narcotics dependence and alcohol dependence.

Among the compounds having the formula (I) relating to the presentinvention, the compound represented by formula (1-1):

[where the symbols have the same meaning as the above] may for examplebe manufactured by the following method.

[where the symbols have the same meaning as the above.](Step 1)

This step is a method of manufacturing compound (3) by reacting anaminocarboxylic acid derivative (1) with an acid anhydride (2).

The amount of acid anhydride (2) used is usually 1 to 10 Eq, butpreferably 2 to 5 Eq, relative to 1 Eq of compound (1).

The reaction temperature is from room temperature to 150° C., butpreferably 100 to 130° C.

The reaction time is usually 1 to 24 hours, but preferably 1 to 6 hours.

The reaction solvent is not particularly limited provided it does notinterfere with the reaction, for example dimethylformamide,dimethylsulfoxide, 1,4-dioxane or toluene, but among these,dimethylformamide and 1,4-dioxane are preferred.

Alternatively, in this step, compound (3) can be manufactured byreacting the aforesaid aminocarboxylic acid derivative (1) and acidanhydride (2) under the aforesaid reaction conditions, without using areaction solvent.

Compound (3) thus obtained can then be passed on to the next step byisolation/purification using a means known in the art, e.g.,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or withoutisolation and purification.

Compound (3) obtained in this step can be manufactured also by thefollowing method.

[where the symbols have the same meaning as the above.]

Step 1) is a method of manufacturing an amido compound represented byformula (1-2) by reacting compound (1) and an acid chloride (2-1) in thepresence of a base.

[where the symbols have the same meaning as the above.]

The acid chloride used in this step may for example be phenylacetylchloride, 1-naphthoyl chloride, 2-naphthoyl chloride, cyclopropanecarbonyl chloride, cyclobutane carbonyl chloride, cyclopentane carbonylchloride or cyclohexane carbonyl chloride.

The amount of compound (2-1) used is usually 1 to 10 Eq, but preferably1 to 1.5 Eq, relative to 1 Eq of compound (1).

The base used may for example be triethylamine, diisopropylamine,pyridine or the like, but preferably diisopropylamine, ethylamine orpyridine.

The reaction temperature is usually 0 to 100° C., but preferably 0 to80° C.

The reaction time is usually 1 to 48 hours, but preferably 3 to 12hours.

The reaction solvent is not particularly limited provided that it doesnot interfere with the reaction, but an inert solvent is preferred.Examples of this inert solvent are pyridine, methylene chloride,chloroform, tetrahydrofuran, 1,4-dioxane, diethyl ether and toluene, butamong these, tetrahydrofuran or pyridine is preferred.

The amide compound (1-2) produced after the reaction is used for thereaction of Step 2) without isolation/purification, after distilling offthe reaction solvent to obtain a residue.

Step 2) is a method of manufacturing compound (4) by reacting theresidue containing the amide compound (1-2) obtained in the aforesaidStep 1) with oxalyl chloride.

In this step, the reaction may be performed by adding a catalytic amountof dimethylformamide to the reaction system.

The amount of oxalyl chloride used is generally 1 to 10 Eq, butpreferably 1 to 3 Eq, relative to 1 Eq of compound (1).

The reaction time is usually 1 to 48 hours, but preferably 1 to 12hours.

The reaction temperature is usually 0 to 100° C., but preferably 0 to50° C.

The reaction solvent is not particularly limited provided that it doesnot interfere with the reaction of Step 2), but an inert solvent ispreferred. Examples of this inert solvent are methylene chloride,chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide,dimethylsulfoxide and toluene, but among these, methylene chloride,chloroform, tetrahydrofuran and toluene are preferred.

The catalytic amount of dimethylformamide is usually 0.01 to 0.5 Eq, butpreferably 0.01 to 0.2 Eq, relative to 1 Eq of compound (1).

Compound (3) thus obtained can then be passed on to the next step byisolation/purification using a means known in the art, e.g.,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or withoutisolation/purification.

(Step 2)

This step is a method of manufacturing compound (5) by reacting compound(3) and compound (4) which were obtained by the aforesaid Step 1.

The amount of compound (4) used is usually 0.5 to 10 Eq, but preferably1 to 3 Eq, relative to 1 Eq of compound (4).

The reaction temperature is usually 60° C. to 160° C., but preferably80° C. to 130° C.

The reaction time is usually 2 to 48 hours, but preferably 5 to 10hours.

The reaction solvent used is not particularly limited provided that itdoes not interfere with the reaction, but an inert solvent such astoluene, 1,4-dioxane, dimethylformamide and dimethylsulfoxide ispreferred.

Specific examples of compound (4) used in this step are 4-aminophenol,5-amino-2-naphthol, 6-amino-2-naphthol, 2-amino-5-hydroxypyrimidine,2-amino-5-hydroxypyridine, 3-amino-6-hydroxypyridine,5-amino-3-hydroxy-1H-1,2,4-triazole, 2-amino-4-hydroxythiazole,3-amino-6-hydroxypyridazine, 2-amino-4-hydroxyoxazole,2-amino-5-hydroxypyrazine, 5-amino-3-hydroxyisothiazole,2-amino-5-hydroxy-1,3,4-thiadiazole,3-amino-5-hydroxy-1,2,4-thiadiazole,5-amino-3-hydroxy-1,3,4-thiadiazole, 5-amino-3-hydroxyisoxazole,2-amino-6-hydroxyquinoline,2-amino-5-hydroxy-1H-benzimidazol-5-amino-2-hydroxy-1H-benzimidazole,2-amino-5-hydroxythiazole[5,4-b]pyridine,2-amino-5-hydroxybenzothiazole, 2-amino-5-hydroxybenzoxazole and3-amino-6-hydroxybenzoxazole.

Compound (5) thus obtained can then be passed on to the next step byisolation/purification using means known in the art, e.g.,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or withoutisolation/purification.

(Step 3)

This step is a method of manufacturing compound (7) by reacting compound(5) obtained in the aforesaid Step 2 with the halogenated compound (6).

The base used may for example be sodium hydrogen carbonate, potassiumcarbonate or sodium hydride, but preferably, potassium carbonate andsodium carbonate.

The amount of base used is usually 1 to 10 Eq, but preferably 1.5 to 5Eq, relative to 1 Eq of compound (5).

The reaction time is usually 1 to 48 hours, but preferably 5 to 12hours.

The reaction temperature is usually 0 to 150° C., but preferably 50° C.to 100° C.

The halogenated compound may for example be 1,3-bromochloropropane or1,4-bromochlorobutane.

Compound (7) thus obtained can then be passed on to the next step byisolation/purification using a means known in the art, e.g.,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or withoutisolation/purification.

(Step 4)

This step is a method of manufacturing compound (I-1) according to thepresent invention by reacting compound (7) obtained in the aforesaidStep 3 with the amino compound (8) in the presence of a base.

The base used in this step may for example be sodium hydrogen carbonate,sodium carbonate, potassium carbonate or sodium hydride, but amongthese, sodium carbonate and potassium carbonate are preferred.

The amount of base used is usually 1 to 10 Eq, but preferably 1 to 5 Eq.

The amount of compound (7) used is usually 1 to 10 Eq, but preferably 2to 5 Eq, relative to 1 Eq of compound (5).

In this step, to increase the reactivity of compound (7), potassiumiodide, tetra-n-butylammonium iodide and the like are preferablyco-present in the reaction system. The amount of potassium iodide usedis usually 0.1 to 10 Eq, but preferably 0.1 to 3 Eq.

The reaction temperature is usually 0 to 150° C., but preferably 50° C.to 100° C.

The reaction time is usually 1 to 48 hours, but preferably 1 to 12hours.

The reaction solvent is not particularly limited provided that it doesnot interfere with the reaction, but an inert solvent such asdimethylformamide, tetrahydrofuran, 1,4-dioxane, acetone or methyl ethylketone is preferred.

Compound (I-1) according to the present invention thus obtained can thenbe isolated/purified using a means known in the art, e.g.,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography.

Compound (I-1) relating to the present invention can be manufacturedalso by the following method:

[where L¹ is a leaving group, and the remaining symbols have the samemeaning as the above].(Step 5)

This step is a method of manufacturing compound (I-1) by reactingcompound (5) obtained by the aforesaid Step 2 with the amino compound(9).

The amino compound (9) used has a leaving group in the molecule. Theleaving group is not particularly limited provided that it detaches toproduce compound (I-1) in the reaction with compound (5). Examples arehalogen atoms such as chlorine and bromine, tosyl and mesyl, but amongthese, bromine and tosyl are preferred.

The amount of the amino compound used is usually 1 to 10 Eq, butpreferably 1 to 3 Eq, relative to 1 Eq of compound (5).

The base used in this step may for example be sodium hydrogen carbonate,sodium carbonate, potassium carbonate or sodium hydride, but amongthese, potassium carbonate and sodium carbonate are preferred.

The reaction temperature is usually 0 to 150° C., but preferably 25° C.to 100° C.

The reaction time is usually 1 to 72 hours, but preferably 3 to 12hours.

The reaction solvent is not particularly limited provided that it doesnot interfere with the reaction, but an inert solvent such asdimethylformamide, tetrahydrofuran, 1,4-dioxane, acetone or methyl ethylketone is preferred.

Compound (I-1) according to the present invention thus obtained can thenbe isolated/purified using a means known in the art, e.g.,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography.

The compound relating to the present invention can be manufactured alsoby the following method using compound (3) obtained in Step 1.

[where the symbols have the same meaning as the above.](Step 6)

This step is a method of manufacturing compound (I-1) relating to thepresent invention by reacting compound (3) obtained by the aforesaidStep 1 with the amino compound (10).

In this step, the amount of compound (10) used is 1 to 10 Eq, butpreferably 1 to 5 Eq, relative to 1 Eq of compound (3).

The reaction temperature is usually −20° C. to 180° C., but preferably0° C. to 130° C.

The reaction time is usually 1 to 72 hours, but preferably 3 to 12hours.

The reaction solvent is not particularly limited provided that it doesnot interfere with the reaction, e.g., an inert solvent such asdimethylformamide, dimethylsulfoxide, acetic acid, 1,4-dioxane ortoluene, but among these, dimethylformamide or acetic acid is preferred.

Compound (I-1) of the present invention which is thus obtained can thenbe passed on to the next step by isolation/purification using a meansknown in the art, e.g., concentration, concentration under reducedpressure, solvent extraction, crystallization, reprecipitation orchromatography.

Compound (10) is not limited to the free amine, but an acid additionsalt may also be used. This acid addition salt may for example be thehydrochloride, tosylate or trifluoroacetate.

Among the compounds (10), the compound represented by formula (10-1):

[where the symbols have the same meaning as the above] can bemanufactured by the following method.

[where T is a hydroxy group or fluorine atom, and the other the symbolshave the same meaning as the above.](Step 6-1)

This step is a method of reacting compound (10A) with compound (10B) tomanufacture compound (10C).

In formula (10A), when T is a hydroxy group (this compound will bereferred to as (10A-1)), the compound (10C) can be manufactured by usingcompound (10A-1) and compound (10B) in a Mitsunobu reaction. TheMitsunobu reaction can be performed by the method described in theliterature (e.g., “The Use of Diethylazodicarboxylate andTriphenylphosphine in Synthesis and Transformation of Natural Products”,Synthesis, Vol. 1, 1981, p. 1-28, by O. Mitsunobu et al.) in thepresence of phosphine and an azo compound, a method based thereon, or acombination of these methods with conventional methods.

The amount of the compound (10B) used is usually 0.5 to 10 Eq, butpreferably 1 to 3 Eq, relative to 1 Eq of compound (10A-1).

The phosphine compound used in this step is usually, for example,triphenylphosphine, triethylphosphine or the like.

The amount of the phosphine compound used is usually 0.5 to 10 Eq, butpreferably 1 to 3 Eq, relative to 1 Eq of compound (10B).

The azo compound used may for example be diethylazodicarboxylate ordiisopropyl azodicarboxylate.

The amount of the azo compound used is usually 0.5 to 10 Eq, butpreferably 1 to 3 Eq, relative to 1 Eq of compound (10B).

The reaction time in this step is usually 1 to 48 hours, but preferably4 to 12 hours.

The reaction temperature in this step is usually from room temperatureto the boiling point of the reaction solvent, but preferably 15° C. to30° C.

The reaction solvent used in this step is not particularly limitedprovided that it does not interfere with the reaction, but specificexamples are tetrahydrofuran and toluene.

In formula (10A), when T is a fluorine atom (this compound will bereferred to as (10A-2)), compound (10C) can be manufactured by reactingcompound (10A-2) with compound (10B) in the presence of a base. The baseused in this step may for example be sodium hydroxide.

The amount of base used is usually 1 to 10 Eq, but preferably 1 to 5 Eq,relative to 1 Eq of compound (10B).

The amount of compound (10B) used is usually 1 to 10 Eq, but preferably2 to 5 Eq, relative to 1 Eq of compound (10A-2).

In this step, to increase the reactivity of compound (10A-2), potassiumiodide and tetra-n-butylammonium iodide are preferably co-present in thereaction system.

The amount of potassium iodide used is usually 0.1-10 Eq, but preferably0.1 to 3 Eq. The reaction temperature is usually from 0° C. to 150° C.,but preferably 50° C. to 100° C.

The reaction time is usually 1 to 48 hours, but preferably 1 to 12hours.

The reaction solvent used in this step is not particularly limitedprovided that it does not interfere with the reaction, but specificexamples are inert solvents such as dimethyl formamide, tetrahydrofuran,1,4-dioxane, acetone and methylethyl ketone.

The compound (10C) thus obtained in this step can then beisolated/purified using a means known in the art, e.g., concentration,concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography.

The compound (10B) used in this step may for example have the formulagiven below.

(Step 6-2)

This step is a method of manufacturing compound (10-1) by catalyticreduction of compound (10C) obtained in the above-mentioned step 6-1,using palladium charcoal as catalyst.

The amount of palladium charcoal used is usually 0.01 to 1 Eq, butpreferably 0.05 to 0.5 Eq, relative to 1 Eq of compound (10C).

The reaction temperature is usually from 0° C. to 80° C.

The reaction time is usually 1 to 48 hours, but preferably 1 to 12hours.

The compound (10-1) thus obtained in this step can then beisolated/purified using a means known in the art, e.g., concentration,concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or passed to thenext step without isolation/purification.

Among the compounds (10), the compound represented by the formula(10-2):

[where the symbols have the same meaning as the above] can bemanufactured by the following method.

(Step 6-3)

In this step, compound (10F) can be manufactured by reacting4-aminophenol (10D) with compound (10E). The reaction used in this stepis the aforesaid Mitsunobu reaction.

The amount of the alcohol compound (10E) used is usually 0.5 to 10 Eq,but preferably 1 to 3 Eq, relative to 1 Eq of compound (10D).

The protective group for the amino group in compound (10E) is notlimited to Boc, and may be any protective group for amino groupsdescribed in the aforesaid “Protective Groups in Organic Synthesis”, byT. W. Green, Vol. 2, John Wiley & Sons, 1991, which acts as a protectivegroup for the amino group in Step 6-3 and can be removed in Step 6-4.

The phosphine compound used in this step is usually, for example,triphenylphosphine or triethylphosphine.

The amount of the phosphine compound used is usually 0.5 to 10 Eq, butpreferably 1 to 3 Eq, relative to 1 Eq of compound (10E).

The azo compound used may for example be diethylazodicarboxylate ordiisopropyl azodicarboxylate. The amount of the azo compound used isusually 0.5 to 10 Eq, but preferably 1 to 3 Eq, relative to 1 Eq ofcompound (10E).

The compound (10E) used in this step may for example be1-Boc-4-piperidinol.

The reaction time is usually 1 to 48 hours, but preferably 4 to 24hours.

The reaction temperature in this step is usually from room temperatureto the boiling point of the reaction solvent, but is preferably 15° C.to 30° C.

The reaction solvent used in this step is not particularly limitedprovided that it does not interfere with the reaction, but specificexamples are tetrahydrofuran and toluene.

The compound (10F) thus obtained can then be isolated/purified using ameans known in the art, e.g., concentration, concentration under reducedpressure, crystallization, solvent extraction, reprecipitation orchromatography, or passed to the next step withoutisolation/purification.

(Step 6-4)

This step is a method of manufacturing compound (10G) by removing theprotective group of the amino group in compound (10F) obtained in theaforesaid Step 6-3.

The protective group can be removed by the method described in theliterature (e.g., “Protective Groups in Organic Synthesis”, by T. W.Green, Vol. 2, John Wiley & Sons, 1991), a method based thereon, or acombination of these methods with conventional methods. When theprotective group of the amino group is a Boc group, the Boc group can beremoved by for example using trifluoroacetic acid.

The compound (10G) thus obtained can then be isolated/purified using ameans known in the art, e.g., concentration, concentration under reducedpressure, crystallization, solvent extraction, reprecipitation orchromatography, or passed to the next step withoutisolation/purification.

(Step 6-5)

This step is a method of manufacturing compound (10I) by reactingcompound (10G) obtained in the Step 6-4 with compound (10H). Thereaction of this step is a so-called reductive amination.

The amount of compound (10H) used in this step is usually 1 to 10 Eq,but preferably 2 to 4 Eq, relative to 1 Eq of compound (10G).

Compound (10H) used in this step may for example be cyclobutanone orcyclopentanone.

The reducing agent used may be an organometallic reagent such as sodiumborohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.

The amount of this reducing agent is usually 1 to 5 Eq, but preferably 1to 3 Eq, relative to 1 Eq of the compound (10G).

A catalytic amount of ZnCl₂ may also be included in the reaction system.

The reaction is usually performed in an inert solvent, such as forexample methanol, ethanol, benzene, toluene, xylene, methylene chloride,chloroform, dimethoxyethane, tetrahydrofuran, dioxane,dimethylformamide, or a mixture thereof.

The reaction temperature is usually from room temperature to the boilingpoint of the solvent used for the reaction, but preferably 20° C. to100° C.

The reaction time is usually 30 minutes to 7 days, but preferably 3hours to 2 days.

The compound (10I) thus obtained in this step can then beisolated/purified using a means known in the art, e.g., concentration,concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or passed to thenext step without isolation/purification.

In the reaction of this step, when R⁶ is a cyclopropyl group, compound(10I) can be manufactured by using(1-methoxycyclopropoxy)-trimethylsilane instead of compound (10H).

(Step 6-6)

This step is a method of manufacturing compound (10-2) by catalyticreduction of compound (10I), using palladium charcoal as catalyst.

The amount of palladium charcoal used is usually 0.01 to 1 Eq, butpreferably 0.05 to 0.5 Eq, relative to 1 Eq of compound (10I).

The reaction temperature is usually 0 to 80° C.

The reaction time is usually 1 to 48 hours, but preferably 1 to 12hours.

Compound (10-2) thus obtained can then be isolated/purified using ameans known in the art, e.g., concentration, concentration under reducedpressure, solvent extraction, crystallization, reprecipitation orchromatography, or passed to the next step withoutisolation/purification.

Other examples of compound (10) are compounds or their acid additionsalts represented by the following formulae.

When it has a substituent group on Ring A, the compound relating to thepresent invention included in formula (I) can be manufactured using astarting material which already has the corresponding substituent. Whenintroduction or deprotection of a protective group in the substituentgroup is required, a method described in the literature, e.g.,“Protective Groups in Organic Synthesis”, T. W. Green, 2nd Edition, JohnWiley & Sons, Ltd., 1991, a method based thereon or a combination ofthese methods with a conventional method, may be used.

The compound relating to the present invention can be manufactured alsoby changing the functional group on Ring A, and introducing/removing aprotective group if required. A protective group in the substituentgroup may be introduced or removed by the method described in“Protective Groups in Organic Synthesis”, T. W. Green, 2nd Edition, JohnWiley & Sons, Ltd., 1991, a method based thereon or a combination ofthese methods with a conventional method. The functional group can bechanged by a method described in the literature, e.g., “ComprehensiveOrganic Synthesis”, Vol. 6, Pergamon Press, 1991, or “ComprehensiveOrganic Transformations”, Richard L et al, VCH Publishers, 1988, amethod based thereon or a combination of these methods with aconventional method.

When Ring A is a benzene ring, Ar is phenyl, i.e. a divalent groupformed by eliminating two hydrogen atoms from benzene, and Ring A has anitro group, the substituent on Ring A can be further modified by thefollowing methods, for example.

[where R⁷ has the same meaning as R¹, and the other symbols have thesame meaning as the above.](Step 7)

In this step, compound (I-4) relating to the present invention which hasa nitro group as substituent, is catalytically reduced using palladiumcharcoal as a catalyst so that the nitro group is converted to amino.

The amount of palladium charcoal used in this step is usually 0.01 to 1Eq, but preferably 0.05 to 0.5 Eq, relative to 1 Eq of compound (I-4).

The reaction temperature is usually 0 to 80° C.

The reaction time is usually 1 Hour to 48 hours, or preferably 1 to 12hours.

Compound (I-5) thus obtained can then be passed on to the next step byisolation/purification using a means known in the art, e.g.,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or withoutisolation/purification.

(Step 8)

This step is a method of manufacturing compound (I-6) by reactingcompound (I-5) obtained in Step 7 with a carboxylic acid compound (11).

This reaction is an amide bonding reaction, and may be the usual amideforming reaction described in the literature, e.g., “Theory andExperiment in Peptide Synthesis”, Nobuo Izumiya; Maruzen, 1983, or“Comprehensive Organic Synthesis”, Vol. 6, Pergamon Press, 1991, amethod based thereon, or a combination of these with a conventionalmethod. Specifically, this can be carried out by those skilled in theart using a known condensation agent, or alternatively, it may beachieved by an ester activation method, mixed acid anhydride method,acid chloride method or carbodiimide method familiar to those skilled inthe art.

Examples of this amide-forming agent are thionyl chloride, oxazalylchloride, N,N-dicyclohexylcarbodiimide, 1-methyl 2-bromopyridiniumiodide, N,N′-carbonyl diimidazole, diphenylphosphoryl chloride,diphenylphosphoryl azide, N,N′-disuccinimidyl carbonate,N,N′-disuccinimidyl oxalate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ethyl chloroformate, isobutyl chlorformateand benzotriazo-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate, but among these, thionyl chloride,1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride,N,N-dicyclohexylcarbodiimide andbenzotriazo-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphateare preferred.

In the amide-forming reaction, a base and a condensation agent may beused together with the aforesaid amide-forming agent.

The base used may be a tertiary aliphatic amine such as trimethylamine,triethylamine, N,N-diisopropylethylamine, N-methyl morpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) and1,5-azabicyclo[4.3.0]nona-5-ene (DBN), or an aromatic amine, e.g.,pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline orisoquinoline, but among these, tertiary aliphatic amines are preferred,and triethylamine or N,N-diisopropylethylamine is particularlypreferred.

The condensation agent used may for example be N-hydroxybenzotriazolehydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboxyimideor 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazol, but among these,N-hydroxybenzotriazole is particularly preferred.

The amount of compound (I-5) used varies with the type of compound andsolvent used, and other reaction conditions, but it is usually 0.1 to 10Eq and preferably 0.5 to 3 Eq relative to 1 Eq of the carboxylic acidderivative (11) or its reactive derivative.

The amount of the amide-forming agent used varies with the type ofcompound and solvent used, and other reaction conditions, but it isusually 1 to 10 Eq and preferably 1 to 3 Eq relative to 1 Eq of thecarboxylic acid derivative (11) or its reactive derivative.

The amount of the condensation agent used varies with the type ofcompound and solvent used, and other reaction conditions, but it isusually 1 to 10 Eq and preferably 1 to 3 Eq relative to 1 Eq of thecarboxylic acid derivative (11) or its reactive derivative.

The amount of base used varies with the type of compound and solventused, and other reaction conditions, but it is usually 1 to 10 Eq andpreferably 1 to 5 Eq.

The reaction solvent in this step may for example be an inert solvent,and is not particularly limited provided that it does not interfere withthe reaction, specific examples being methylene chloride, chloroform,1,2-dichloroethane, N,N-dimethylformamide, ethyl acetate ester, aceticacid methyl ester, acetonitrile, benzene, xylene, toluene, 1,4-dioxane,tetrahydrofuran, dimethoxyethane or mixed solvents thereof, but from theviewpoint of suitable reaction temperature maintenance, methylenechloride, chloroform, 1,2-dichloroethane, acetonitrile orN,N-dimethylformamide are for example preferred.

The reaction temperature in this step is usually from −78° C. to theboiling point of the solvent, but it is preferably 0 to 30° C.

The reaction time in this step is usually 0.5 to 96 hours, butpreferably 3 to 24 hours.

The base, amide-forming agent and condensation agent used in this stepcan be combined together.

Compound (I-6) according to the present invention thus obtained can thenbe isolated/purified using a means known in the art, e.g.,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography.

When the substituent group on Ring A is an aryl group or a heteroarylgroup, it can be manufactured by the following method using compound(I-7) of the present invention having a halogen atom on Ring A.

[where X is a halogen atom, X⁴ is an aryl or a heteroaryl group, and theother symbols have the same meaning as the above.](Step 9)

This step is a method of manufacturing compound (I-8) of the presentinvention having an aryl or a heteroaryl substituent group on Ring A bypreparing another derivative of compound (I-7) relating to the presentinvention which has a halogen atom such as chlorine, bromine or iodineon Ring A.

To convert compound (I-7) to compound (I-8), a Suzuki coupling can beperformed.

More specifically, compound (I-8) according to the present inventionhaving an aryl or a heteroaryl substituent group on Ring A can bemanufactured by reacting compound (I-7) having a halogen atom on Ring Awith X⁴—B(OH)₂ in the presence of a base, a palladium catalyst and, ifrequired, a phosphine ligand.

This step may be performed by the method described in “Angew. Chem.,Int. Ed. Eng.”, 1999, 38(16), pp. 2413-2416, by J. P. Wolfe, S. L.Buchwald et al., by a method based thereon, or by a combination of thesewith a conventional method.

The base used may for example be sodium carbonate, potassium carbonate,cesium carbonate, cesium fluoride, potassium fluoride or sodiumfluoride.

The amount of base used is usually 1 to 10 Eq, but preferably 1 to 3 Eq,relative to 1 Eq of compound (I-7).

The palladium catalyst used may for example be Pd(PPh₃)₄, Pd(OAc)₃,Pd₃(dba)₃ or PdCl₃(PPh₃)₃.

The amount of palladium catalyst used is usually 0.01 to 0.5 Eq, butpreferably 0.05 to 0.2 Eq, relative to 1 Eq of compound (I-7).

The phosphine ligand used may for example be PPh₃, P(o-tol)₃, P(tBu)₃,2-[di(t-butyl)phosphino]-1,1′-biphenyl,2-[di(t-butyl)phosphino]-2′-dimethylamino-1,1′-biphenyl,2-[dicyclohexylphosphino]-1,1′-biphenyl, or2-[dicyclohexylphosphino]-2′-dimethylamino-1,1′-biphenyl.

The borane compound used may be a commercial aryl boron derivative orheteroaryl boron derivative such as phenyl boric acid, a phenylboricacid ester or dialkylphenyl borane, or the target boron derivative canbe manufactured by a known method, a method based thereon or acombination of these with a conventional method.

The amount of boron compound used is usually 1 to 10 Eq, but preferably2 to 5 Eq.

The amount of the boric acid compound X⁴—B(OH)₂ (X⁴ is the same as theabove) is usually 1 to 10 Eq, but preferably 2 to 5 Eq.

Compound (I-9) relating to the present invention can be manufactured bythe following method.

[where the symbols have the same meaning as the above.]

The reaction in this step is known as the Mitsunobu reaction, and is amethod described in the literature, e.g., Mitsunobu. O, “Use ofdiethylazodicarboxylate and triphenylphosphine in synthesis andtransformation of natural products”, Synthesis, Vol. 1, 1981, p. 1-28, amethod based thereon, or a combination of these with a conventionalmethod, in the presence of a phoshine compound and an azo compound.

The amount of the alcohol compound (12) X²OH used in this step isusually 0.5 to 10 Eq, but preferably 1 to 3 Eq, relative to 1 Eq ofcompound (5).

The phosphine compound used in this step is usually for exampletriphenylphosphine or triethylphosphine.

The amount of phosphine compound used is usually 0.5 to 10 Eq, butpreferably 1 to 3 Eq, relative to 1 Eq of (5).

The azo compound used may for example be diethylazodicarboxylate ordiisopropyl azodicarboxylate.

The amount of azo compound used is usually 0.5 to 10 Eq, but preferably1 to 3 Eq, relative to 1 Eq of compound (5).

The reaction time in this step is usually 1 to 48 hours, but preferably4 to 12 hours.

The reaction temperature in this step is usually from room temperatureto the boiling point of the reaction solvent, but preferably 15° C. to30° C.

The reaction solvent in this step is not particularly limited if it doesnot interfere with the reaction, but specific examples aretetrahydrofuran or toluene.

Compound (I-9) thus obtained can then be isolated/purified using a meansknown in the art, e.g., concentration, concentration under reducedpressure, solvent extraction, crystallization, reprecipitation orchromatography.

The compound relating to the present invention represented by formula(I) can easily be isolated/purified by the usual isolation/purificationmeans. This means may for example be solvent extraction,recrystallization, reprecipitation, column chromatography orfractionation thin layer chromatography.

These compounds can be made into salts or esters which arepharmaceutically acceptable by conventional methods, or conversely, thefree compounds may be prepared from salts or esters by conventionalmethods.

The fused ring 4-oxopyrimidine derivative of the present invention canexist as a pharmaceutically acceptable salt, and this salt can bemanufactured according to conventional methods using the compoundrepresented by the aforesaid formula (I). Examples of this acid additionsalt are halide acid salts such as the hydrochloride, hydrofluoride,hydrobromide and hydroiodide; inorganic acid salts such as the nitrate,perchlorate, sulfate, phosphate and carbonate; lower alkylsulfonic acidsalts such as the methane sulfonic acid salt, trifluoromethane sulfonicacid salt and ethane sulfonic acid salt; arylsulfonates, such as thebenzenesulfonic acid salt and p-toluenesulfonic acid salt; salts oforganic acids, such as the fumarate, succinate, citrate, tartrate,oxalate and maleate; and salts of aminoacids such as the glutamate andaspartate.

Examples of a base addition salt are salts of alkali metals such assodium and potassium, salts of alkaline earth metals such as calcium,and magnesium, and salts of organic bases such as ammonium, guanidine,triethylamine and dicyclohexylamine. The compound of the presentinvention may further exist as a free compound, a hydrate of a salt, ora solvate.

The compound represented by formula (I) may be administered orally ornon-orally may be used.

When the compound of the present invention is used clinically, it mayalso be combined with other pharmaceutically acceptable additives invarious pharmaceutical preparations depending on the mode ofadministration. These additives may be those usually used as additivesin pharmaceutical preparations, such as gelatin, lactose, white softsugar, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, amylum maydis, microcrystallinewax, white vaseline, magnesium aluminometasilicate, anhydrous calciumphosphate, citric acid, sodium tricitrate, hydroxypropylcellulose,sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acidester, polyoxyethylene, hydrogenated castor oil, polyvinyl pyrrolidone,magnesium stearate, light anhydrous silicic acid, talc, vegetable oil,benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol,cyclodextrin or hydroxypropyl cyclodextrin.

The form of administration of this pharmaceutical preparation as amixture with these additives may be a solid preparation, such astablets, capsules, granules, powders or suppositories, or a liquidpreparation such as syrups, elixirs or injections, and these can beprepared according to the methods usually used for pharmaceuticalpreparations. In the case of a liquid preparation, it may be dissolvedor suspended in water or other suitable media. In particular, in thecase of an injection, it may be dissolved or suspended in physiologicalsaline or grape sugar, and buffers and preservatives may be added ifrequired. These pharmaceutical preparations may contain 1.0 to 100 wt %,but preferably 1.0 to 60 wt %, of the compound of the present inventionrelative to the total preparation.

Pharmaceutical preparations containing the compound of the presentinvention can be made, for example, according to the followingpharmaceutical examples.

PHARMACEUTICAL EXAMPLE 1

10 parts of the compound of Example 1, 15 parts of heavy magnesium oxideand 75 parts of lactose are mixed uniformly to manufacture a powder orparticulate of 350 μm or less. This powder is inserted into a capsulecontainer to manufacture a capsule.

PHARMACEUTICAL EXAMPLE 2

45 parts of the compound of Example 1, 15 parts of starch, 16 parts oflactose, 21 parts of crystalline celluloses, 3 parts of polyvinylalcohol and 30 parts of distilled water is mixed uniformly, crushed,dried and graded to obtain granules of diameter 1410 to 177 μm.

PHARMACEUTICAL EXAMPLE 3

After producing granules by the same method as that of PharmaceuticalExample 2, 3 parts of calcium stearate is added to 96 parts of thesegranules and compressed into tablets of 10 mm diameter.

PHARMACEUTICAL EXAMPLE 4

10 parts of crystalline cellulose and 3 parts of calcium stearate areadded to 90 parts of the granules obtained in Pharmaceutical Example 2,compressed into tablets of diameter 8 mm and sirup gelatin/precipitatedcalcium carbonate mixed suspension is added to produced sugar-coatedtablets.

These pharmaceutical preparations may also contain other therapeuticallyuseful compounds.

The compound of the present invention may be used in conjunction withother agents useful for the treatment of metabolic disorders and/oreating disorders. These ingredients in these combinations may beadministered at different times or simultaneously during the treatment,or may be administered as different medications or as a singlepharmaceutical preparation. The present invention should therefore beunderstood to include simultaneous administration or administration atdifferent times, and “administration” in the context of the presentinvention should be interpreted as such. The range of combinationsbetween the compound of the present invention and other agents useful inmetabolic disorders and/or eating disorders, in principle coverscombinations with all pharmaceutical preparations useful in thetreatment of metabolic disorders and/or eating disorders.

The compound of the present invention can be used in combination withother drugs effective in the treatment, prevention, or control ofdisorders, such as hypertension, hypertension associated with obesity,hypertension-related disorders, cardiac hypertrophy, left ventricularhypertrophy, and metabolic syndrome, obesity and obesity-relateddisorders. In the prophylaxis or therapy of these disorders, such otherdrugs (concomitant drugs) can be administered simultaneously, separatelyor successively. When used simultaneously with one, two or more otherdrugs, it can be administered as a single dose. However, in combinationtherapy, the composition containing the compound of the presentinvention and concomitant drugs may be administered simultaneously,separately or successively as different packages. These may also beadministered with a time lag.

The dosage amount of concomitant drugs may be based on the dosage usedin clinical practice, and may be selected as appropriate, depending onthe patient, the route of administration, the disease or thecombination. The administration modality of the concomitant drug is notparticularly limited, it being sufficient that the compound of thepresent invention and the concomitant drug are combined in some way.Examples of the administration modality are: 1) administration of asingle pharmaceutical preparation obtained by simultaneously blendingthe compound of the present invention with another drug; 2) simultaneousadministration of two types of pharmaceutical preparation, obtained byseparately preparing the compound of the present invention and anotherdrug, by the same route of administration; 3) administration of twotypes of pharmaceutical preparation, obtained by separately preparingthe compound of the present invention and another drug by the same routeof administration, with a time lag; 4) simultaneous administration oftwo types of pharmaceutical preparation, obtained by separatelypreparing the compound of the present invention and another drug, by adifferent route of administration, and 5) administration of two types ofpharmaceutical preparation, obtained by separately preparing thecompound of the present invention and another drug, by a different routeof administration with a time lag (e.g., administration of the compoundof the present invention followed by the other drug, or in the reverseorder).

The blending ratio of the compound of the present invention and theother drug may be suitably selected depending on the drugs beingadministered, route of administration and disease.

Examples of concomitant drugs used in the present invention areanti-diabetic agents, lipid lowering agents, anti-hypertensive agentsand anti-obesity agents. Two or more of these concomitant drugs may becombined in a suitable proportion.

Examples of anti-diabetic agents are:

-   1) PPARγ agonists such as glitazones (e.g. ciglitazone;    darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone;    rosiglitazone; troglitazone; BRL49653; CLX-0921; 5-BTZD, and the    like), and GW-0207, LG-100641, and LY-300512, and the like;-   2) biguanides such as buformin; metformin; and phenformin, and the    like;-   3) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;-   4) sulfonylureas such as acetohexamide; chlorpropamide; diabinese;    glibenclamide; glipizide; glyburide; glimepiride; gliclazide;    glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide,    and the like;-   5) meglitinides such as repaglinide, and nateglinide, and the like;-   6) alpha glucoside hydrolase inhibitors such as acarbose; adiposine;    camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q;    salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the    like;-   7) alpha-amylase inhibitors such as tendamistat, trestatin, and    Al-3688, and the like;-   8) insulin secreatagogues such as linogliride; and A-4166, and the    like;-   9) fatty acid oxidation inhibitors, such as clomoxir, and etomoxir,    and the like;-   10) A2 antagonists, such as midaglizole; isaglidole; deriglidole;    idazoxan; earoxan; and fluparoxan, and the like;-   11) insulin or insulin mimetics, such as biota, LP-100, novarapid,    insulin detemir, insulin lispro, insulin glargine, insulin zinc    suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)    (insulintropin); and GLP-1 (7-36)—NH₂), and the like;-   12) non-thiazolidinediones such as JT-501, and farglitazar    (GW-2570/GI-262579), and the like;-   13) PPARα/γ dual agonists such as CLX-0940, GW-1536, GW1929,    GW-2433, KRP-297, L-796449, LR-90, and SB 219994, and the like;-   14) other insulin sensitizing drugs; and-   15) VPAC2 receptor agonists.

Examples of lipid lowering agents are:

-   1) bile acid sequestrants such as, cholestyramine, colesevelem,    colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran;    Colestid®; LoCholest®; and Questran®, and the like;-   2) HMG-CoA reductase inhibitors such as atorvastatin, itavastatin,    fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin,    simvastatin, and ZD-4522, and the like;-   3) HMG-CoA synthase inhibitors;-   4) cholesterol absorption inhibitors such as stanol esters,    beta-sitosterol, sterol glycosides such as tiqueside; and    azetidinones such as ezetimibe, and the like;-   5) acyl coenzyme A-cholesterol acyl transferase (ACAT) inhibitors    such as avasimibe, eflucimibe, KY505, SMP 797, and the like;-   6) CETP inhibitors such as JTT 705, torcetrapib, CP 532,632,    BAY63-2149, SC 591, SC 795, and the like;-   7) squalene synthetase inhibitors;-   8) anti-oxidants such as probucol, and the like;-   9) PPARα agonists such as beclofibrate, benzafibrate, ciprofibrate,    clofibrate, etofibrate, fenofibrate, gemcabene, and gemfibrozil, GW    7647, BM 170744, LY518674; and other fibric acid derivatives, such    as Atromid®, Lopid® and Tricor®, and the like;-   10) FXR receptor modulators such as GW 4064, SR 103912, and the    like;-   11) LXR receptor such as GW 3965, T9013137, and XTC0179628, and the    like;-   12) lipoprotein synthesis inhibitors such as niacin;-   13) renin angiotensin system inhibitors;-   14) PPARδ partial agonists;-   15) bile acid reabsorption inhibitors, such as BARI 1453, SC435,    PHA384640, S8921, AZD7706, and the like;-   16) PPARδ agonists such as GW 501516, and GW 590735, and the like;-   17) triglyceride synthesis inhibitors;-   18) microsomal triglyceride transport (MTTP) inhibitors, such as    inplitapide, LAB687, and CP346086, and the like;-   19) transcription modulators;-   20) squalene epoxidase inhibitors;-   21) low density lipoprotein (LDL) receptor inducers;-   22) platelet aggregation inhibitors;-   23) 5-LO or FLAP inhibitors; and-   24) niacin receptor agonists.

Examples of anti-hypertensive agents are:

-   1) diuretics, such as thiazides, including chlorthalidone,    chlorthiazide, dichlorophenamide, hydroflumethiazide, indapamide,    and hydrochlorothiazide; loop diuretics, such as bumetamide,    ethacrynic acid, furosemide, and torsemide; potassium sparing    agents, such as amiloride, and triamterene; and aldosterone    antagonists, such as spironolactone, epirenone, and the like;-   2) beta-adrenergic blockers such as acebutolol, atenolol, betaxolol,    bevantolol, bisoprolol, bopindolol, carteolol, carvedilol,    celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol,    penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol,    and timolol, and the like;-   3) calcium channel blockers such as amlodipine, aranidipine,    azelnidipine, barnidipine, benidipine, bepridil, cinaldipine,    clevidipine, diltiazem, efonidipine, felodipine, gallopamil,    isradipine, lacidipine, lemildipine, lercanidipine, nicardipine,    nifedipine, nilvadipine, nimodepine, nisoldipine, nitrendipine,    manidipine, pranidipine, and verapamil, and the like;-   4) angiotensin converting enzyme (ACE) inhibitors such as    benazepril; captopril; cilazapril; delapril; enalapril; fosinopril;    imidapril; losinopril; moexipril; quinapril; quinaprilat; ramipril;    perindopril; perindropril; quanipril; spirapril; tenocapril;    trandolapril, and zofenopril, and the like;-   5) neutral endopeptidase inhibitors such as omapatrilat, cadoxatril    and ecadotril, fosidotril, sampatrilat, AVE7688, ER4030, and the    like;-   6) endothelin antagonists such as tezosentan, A308165, and YM62899,    and the like;-   7) vasodilators such as hydralazine, clonidine, minoxidil, and    nicotinyl alcohol, and the like;-   8) angiotensin II receptor antagonists such as candesartan,    eprosartan, irbesartan, losartan, pratosartan, tasosartan,    telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270, and the    like;-   9) α/β adrenergic blockers as nipradilol, arotinolol and amosulalol,    and the like;-   10) alpha 1 blockers, such as terazosin, urapidil, prazosin,    bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHIP 164,    and XEN010, and the like;-   11) alpha 2 agonists such as lofexidine, tiamenidine, moxonidine,    rilmenidine and guanobenz, and the like; and-   12) aldosterone inhibitors, and the like.

Examples of anti-obesity agents are:

-   1) 5HT (serotonin) transporter inhibitors, such as paroxetine,    fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine;-   2) NE (norepinephrine) transporter inhibitors, such as GW 320659,    despiramine, talsupram, and nomifensine;-   3) CB-1 (cannabinoind-1 receptor) antagonist/inverse agonists, such    as rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo),    BAY 65-2520 (Bayer), and SLV 319 (Solvay), and those disclosed in    U.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122,    5,112,820, 5,292,736, 5,624,941 and U.S. Pat. No. 6,028,084; and PCT    Patent Application Nos. WO 96/33159, WO 98/33765, WO 98/43636, WO    98/43635, WO 01/09120, WO 01.96330, WO 98/31227, WO 98/41519, WO    98/37061, WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO    01/58869, WO 02/076949, WO 01/64632, WO 01/64633, WO 01/64634, WO    03/006007 and WO 03/007887; and EPO Application No. EP-658546;-   4) ghrelin antagonists, such as those disclosed in WO 01/87335, and    WO 02/08250;-   5) H3 (histamine H3) antagonist/inverse agonists, such as    thioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,    clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and    A331440, and those disclosed in WO02/15905; and    O-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et    al., Pharmazie, 55: 349-55 (2000)), piperidine-containing histamine    H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56: 927-32    (2001), benzophenone derivatives and related compounds (Sasse, A. et    al., Arch. Pharm. (Weinheim) 334: 45-52 (2001)), substituted    N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55: 83-6    (2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem.,    43: 3335-43 (2000));-   6) melanin-concentrating hormone 1 receptor (MCH1R) antagonists,    such as T-226296 (Takeda), SNP-7941 (Synaptic), and those disclosed    in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO    02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO    02/51809, WO 02/083134, WO 02/094799 and WO 03/004027, and Japanese    Patent Application No. JP 13226269;-   7) MCH2R (melanin concentrating hormone 2R) agonist/antagonists;-   8) NPY1 (neuropeptide Y Y1) antagonists, such as BIBP3226, J-115814,    BIBO 3304, LY-357897, CP-671906, and GI-264879A; and those disclosed    in U.S. Pat. No. 6,001,836; and PCT Patent Application Nos. WO    96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO    01/85173 and WO 01/89528;-   9) NPY5 (neuropeptide Y Y5) antagonists, such as 152,804,    GW-569180A, GW-594884A, GW-587081×, GW-548118×; FR235,208; FR226928,    FR240662, FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897,    LY-366377, PD-160170, SR-120562A, SR-120819A, JCF-104, and H409/22;    and those compounds disclosed in U.S. Pat. Nos. 6,140,354,    6,191,160, 6,258,837, 6,313,298, 6,337,332, 6,329,395 and 6,340,683;    U.S. Pat. Nos. 6,326,375; 6,329,395; 6,337,332; 6,335,345; European    Patent Nos. EP-01010691, and EP-01044970; and PCT Patent Publication    Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO    97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO    00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO    01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO    01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO    01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648 and WO    02/094789; and Norman et al., J. Med. Chem. 43: 4288-4312 (2000);-   10) leptin, such as recombinant human leptin (PEG-OB, Hoffman La    Roche) and recombinant methionyl human leptin (Amgen);-   11) leptin derivatives, such as those disclosed in U.S. Pat. Nos.    5,552,524, 5,552,523, 5,552,522 and 5,521,283; and PCT Patent    Publication Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516,    WO 96/23517, WO 96/23518, WO 96/23519 and WO 96/23520;-   12) opioid antagonists, such as nalmefene (Revex®),    3-methoxynaltrexone, naloxone, and naltrexone; and those disclosed    in WO 00/21509;-   13) orexin antagonists, such as SB-334867-A; and those disclosed in    WO 01/96302, WO 01/68609, WO 02/51232, WO 02/51838 and WO 03/023561;-   14) BRS3 (bombesin receptor subtype 3) agonists;-   15) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI    181771, JMV-180, A-71378, A-71623 and SR146131, and those disclosed    in U.S. Pat. No. 5,739,106;-   16) CNTF (ciliary neurotrophic factors), such as GI-181771    (Glaxo-SmithKline); SR146131 (Sanofi Synthelabo); butabindide; and    PD170,292, PD149164 (Pfizer);-   17) CNTF derivatives, such as axokine (Regeneron); and PCT    Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813;-   18) GHS (growth hormone secretagogue receptor) agonists, such as    NN₇O₃, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and    L-163,255, and those disclosed in U.S. Pat. No. 6,358,951, U.S.    Patent Application Nos. 2002/049196 and 2002/022637; and PCT Patent    Application Nos. WO 01/56592 and WO 02/32888;-   19) 5HT2c (serotonin receptor 2c) agonists, such as BVT933,    DPCA37215, IK264; PNU22394; WAY161503, R-1065, and YM348; and those    disclosed in U.S. Pat. No. 3,914,250; and PCT Patent Application    Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO    02/44152; WO 02/51844, WO 02/40456 and WO 02/40457;-   20) Mc3r (melanocortin 3 receptor) agonists;-   21) Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036    (Chiron); ME-10142, and ME-10145 (Melacure), and those disclosed in    WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 01/70708, WO    01/70337, WO 01/91752, WO 02/059095, WO 02/059107, WO 02/059108, WO    02/059117, WO 02/12166, WO 02/11715, WO 02/12178, WO 02/15909, WO    02/068387, WO 02/068388, WO 02/067869, WO 03/007949 and WO    03/009847;-   22) monoamine reuptake inhibitors, such as sibutratmine    (Meridia®/Reductil®) and a salt thereof, and those compounds    disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570, and 5,436,272, and    U.S. Patent Publication No. 2002/0006964, and PCT Patent Application    Nos. WO 01/27068 and WO 01/62341;-   23) serotonin reuptake inhibitors, such as dexfenfluramine,    fluoxetine, and those in U.S. Pat. No. 6,365,633, and PCT Patent    Application Nos. WO 01/27060, and WO 01/162341;-   24) GLP-1 (glucagon-like peptide 1) agonists;-   25) Topiramate (Topimax®);-   26) phytopharm compound 57 (CP 644,673);-   27) ACC2 (acetyl-CoA carboxylase-2) inhibitors;-   28) β3 (beta adrenergic receptor 3) agonists, such as AD9677/TAK677    (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568,    BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecadrine,    Zeneca D7114, and SR 59119A, and those disclosed in U.S. patent    application No. 5,705,515, U.S. Pat. No. 5,451677; and PCT Patent    Application Nos. WO 01/74782 and WO 02/32897;-   29) DGAT1 (diacylglycerol acyltransferase 1) inhibitors;-   30) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;-   31) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75;-   32) PDE (phosphodiesterase) inhibitors, such as theophylline,    pentoxifylline, zaprinast, sildenafil, amrinone, milrinone,    cilostamide, rolipram, and cilomilast;-   33) thyroid hormone β agonists, such as KB-2611 (KaroBioBMS), and    those disclosed in PCT Application No. WO 02/15845, and Japanese    Patent Application No. JP 2000256190;-   34) UCP-1 (uncoupling protein 1), 2, or 3 activators, such as    phytanic acid,    4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic    acid (TTNPB), and retinoic acid; and those disclosed in WO 99/00123;-   35) acyl-estrogens, such as oleoyl-estrone, disclosed in del    Mar-Grasa, M. et al., Obesity Research, 9: 202-9 (2001);-   36) glucocorticoid antagonists;-   37) 11β HSD-1 (11-beta-hydroxy-steroid dehydrogenase type 1)    inhibitors, such as BVT-3498, BVT 2733, and those compounds    disclosed in WO 01/90091, WO 01/90090 and WO 01/90092;-   38) SCD-1 (stearoyl-CoA desaturase-1) inhibitors;-   39) dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucine    thiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL    225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444; and    the compounds disclosed in WO 03/004498, WO 03/004496, EP 1 258 476    WO 02/083128, WO 02/062764, WO 03/000250, WO 03/002530, WO    03/002531, WO 03/002553, WO 03/002593, WO 03/000180, and WO    03/000181;-   40) lipase inhibitors, such as tetrahydrolipstatin    (orlistat/Xenical®), Triton WR1339, RHC80267, lipstatin, teasaponin,    and diethylumbelliferyl phosphate, FL-386, WAY-121898, Bay-N-3176,    valilactone, esteracin, ebelactone A, ebelactone B, and RHC 80267,    and those disclosed in PCT Application No. WO 01/77094, and U.S.    Pat. Nos. 4,598,089. 4,452,813, 5,512,565, 5,391,571, 5,602,151,    4,405,644, 4,189,438 and 4,242,453; 41) fatty acid transporter    inhibitors;-   42) dicarboxylate transporter inhibitors;-   43) glucose transporter inhibitors;-   44) phosphate transporter inhibitors;-   45) melanocortin agonists, such as Melanotan II or those described    in WO 99/64002 and WO 00/746799;-   46) melanin concentrating hormone antagonists;-   47) galanin antagonists;-   48) CCK agonists;-   49) corticotropin-releasing hormone agonists; and-   50) phosphodiesterase-3B (PDE3B) inhibitors; and the like.

The above combinations include combinations of a composition of thepresent invention not only with one other active compound, but also withtwo or more other active compounds. Non-limiting examples includecombinations of the compositions of the present invention with one, twoor more active compounds (concomitant drugs) selected fromlipid-lowering agents, and anti-hypertensive agents. Combinations of thecompositions of the present invention with one, two or more activecompounds (concomitant drugs) selected from lipid lowering agents, andanti-diabetic agents are useful to treat, control or prevent metabolicsyndrome. In particular, compositions comprising an anti-obesity agent,an anti-hypertensive agent, in addition to an anti-diabetic agent and/ora lipid lowering agent will be useful to synergistically treat, controlor prevent metabolic syndrome.

When the compound of the present invention is used in a clinicalsetting, the dose and frequency of administration depend on thepatient's sex, age, weight, condition, and the type and extent of theeffect it is desired to obtain. However, in oral administration to anadult, it is 0.01-100 mg/kg but preferably 0.3-1 mg/kg per dayadministered in one or several doses, and in non-oral administration toan adult, it is 0.001-10 mg/kg but preferably 0.001-0.1 mg/kg per dayadministered in one or several doses.

The physician, veterinarian or clinician can easily determine aneffective pharmacological amount of the drug to prevent, suppress orstop a disease process.

EXAMPLES

The present invention will now be described by means of examples, but itwill be understood that the present invention is not limited in any waythereby.

For the thin layer chromatography of the examples, Silicagel 60F245(Merck) was used for the plates and a UV detector was used as thedetection method. Wakogel™ C-300 (Wako Pure Chem.) was used as silicagel for columns and LC-SORBTM SP-B-ODS (Chemco) or YMC-GEL™ODS-AQ120-S50 (Yamamura Chemical Research Institute) was used as silicagel for reverse phase columns. The mass spectrum was measured by theelectrospray ionizing method (ESI) using QuattroII (product of MicromassCo.) When measuring the NMR spectrum in heavy dimethylsulfoxidesolution, measurements were performed using a Gemini-200 (200 MHz,Varian), Gemini-300 (300 MHz, Varian), Mercury 400 (400 MHz, Varian) orInova 400 (400 MHz, Varian) spectrometer with dimethylsulfoxide asinternal reference, and all δ values were expressed as ppm.

The meanings of the abbreviations in the following examples are asfollows:

-   i-Bu: isobutyl-group-   n-Bu: n-butyl-   t-Bu: t-butyl-   Me: methyl-group-   Et: ethyl-group-   Ph: phenyl-group-   i-Pr: isopropyl group-   n-Pr: n-propyl group-   CDCl₃: heavy-chloroform-   CD₃OD: heavy-methanol-   DMSO-d6: heavy-dimethylsulfoxide.

The meanings of the abbreviations on the nuclear magnetic resonancespectrum are as follows:

-   s: singlet-   d: doublet-   dd: double-doublet-   t: triplet-   m: multiplet-   br: broad-   q: quartet-   J: coupling-constant-   Hz: a hertz

Example 12-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone (1)Manufacture of 2-ethyl-4H-3,1-benzoxazin-4-one

Anthranilic acid (10 g, 72.9 mmol) and propionic anhydride (20.9 g, 160mmol) were mixed and stirred at 130° C. for 2 hours. The reactionsolution was concentrated under reduced pressure, the residue wasdissolved in methylene chloride, the organic phase was washed withsaturated sodium hydrogen carbonate aqueous solution and then distilledwater and dried with anhydrous sodium sulfate. The target compound (12.5g, 98%) was obtained as a colorless solid by filtering off the sodiumsulfate and concentrating to dryness.

(2) Manufacture of 2-ethyl-3-(4-hydroxyphenyl)-4-(3H)-quinazolinone

2-ethyl-4H-3,1-benzoxazin-4-one (6.5 g, 37.1 mmol) and 4-aminophenol(4.05 g, 37.1 mmol) were dissolved in dimethylformamide (18 mL) andstirred at 140° C. for 10 hours. After leaving to cool to roomtemperature, distilled water (94 mL) was added, and the solidprecipitate was filtered off. The product was recrystallized (ethanol)and the target compound (6.52 g, 66%) was obtained as light browncrystals.

(3) Manufacture of2-ethyl-3-[4-(3-chloropropoxy)phenyl]-4(3H)-quinazolinone

2-ethyl-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (17.9 g, 67.5 mmol),1,3-bromochloropropane (12.1 g, 70.3 mmol) and potassium carbonate (19.7g, 143 mmol) were mixed in dimethylformamide (180 mL) and stirred at 80°C. for 2 hours.

After evaporating the solvent under reduced pressure, ethyl acetate anddistilled water were added. After extracting with ethyl acetate, theorganic phase was washed with distilled water and dried with anhydroussodium sulfate.

The sodium sulfate was filtered off, the filtrate was evaporated underreduced pressure and the obtained solid was washed by ethanol to obtainthe target compound (19.1 g, 82%) as a light brown solid.

(4) Manufacture of2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

2-ethyl-3-[4-(3-chloropropoxy)phenyl]-4(3H)-quinazolinone (19 g, 55.6mmol), piperidine (23.7 g, 278 mmol), potassium carbonate (11.5 g, 83.4mmol) and potassium iodide (13.8 g, 83.4 mmol) were mixed indimethylformamide (400 mL) and stirred at 80° C. for 24 hours.

The solvent was evaporated under reduced pressure, the residue wasdissolved in ethyl acetate and the organic phase was washed withdistilled water and dried with anhydrous sodium sulfate.

After purifying with silica gel column chromatography(chloroform/methanol=30/1), the title compound (10.1 g, 47%) wasobtained as colorless crystals by recrystallizing from diethylether/heptane.

¹HNMR (400 MHz,CDCl₃,δppm): 1.22 (3H,t,J=7.2 Hz), 1.41-1.47 (2H,m),1.57-1.64 (4H,m), 1.97-2.05 (2H,m), 2.36-2.58 (BH,m), 4.06 (2H,t,J=6.4Hz), 7.02 (2H,d,J=8.4 Hz), 7.12 (2H,d,J=8.4 Hz), 7.43 (1H,t,J=7.6 Hz),7.67-7.78 (2H,m), 8.25 (1H,d,J=8.4 Hz)

The compound of Example 2-16 can be manufactured by the same method asthat of Example 1, a method based thereon or a combination of these anda conventional method, using the corresponding anthranilic acid, acidanhydride, aminophenol, 1,3-bromochloroalkane and amine as startingmaterials.

Example 22-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and piperidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.55 (2H,m), 1.50-1.64 (4H,m),1.97-2.04 (2H,m), 2.25 (3H,s), 2.37-2.46 (4H,brs), 2.49 (2H,t,J=6.8 Hz),4.06 (2H,t,J=6.8 Hz), 7.03 (2H,d,J=8.4 Hz), 7.12 (2H,d,J=8.4 Hz), 7.44(1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.8 Hz), 7.74 (1H,t,J=8.0 Hz), 8.25(1H,d,J=8.0 Hz)

Example 32-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and pyrrolidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.49 (2H,m), 1.58-1.66 (4H,m), 2.25(3H,s), 2.48-2.58 (4H,brs), 2.81 (2H,t,J=6.0 Hz), 4.15 (2H,t,J=5.6 Hz),7.03 (2H,d,J=9.2 Hz), 7.13 (2H,d,J=9.2 Hz), 7.44 (1H,t,J=8.0 Hz), 7.65(1H,d,J=8.0 Hz), 7.72 (1H,t,J=7.2 Hz), 8.25 (1H,d,J=8.0 Hz)

Example 43-{4-[3-(diethylamino)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and diethylamine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.04 (6H,t,J=7.2 Hz), 1.91-2.00 (2H,m), 2.25(3H,s), 2.55 (4H,q,J=6.8 Hz), 2.63 (2H,t,J=6.8 Hz), 4.06 (2H,t,J=6.4Hz), 7.03 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.4 Hz),7.65 (1H,d,J=8.0 Hz), 7.74 (1H,t,J=8.0 Hz), 8.25 (1H,d,J=8.0 Hz)

Example 52-methyl-3-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 2-methylpyrrolidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.10 (3H,d,J=6.4 Hz), 1.37-1.46 (1H,m),1.65-1.72 (2H, m), 1.86-1.97 (1H,m), 1.99-2.17 (3H,m), 2.17-2.24 (1H,m),2.25 (3H,s), 2.26-2.33 (1H,m), 2.96-3.03 (1H,m), 3.16-3.23 (1H,m),4.05-4.10 (2H,m), 7.03 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.44(1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.8 Hz), 7.74 (1H,t,J=8.0 Hz), 8.25(1H,d,J=8.0 Hz)

Example 63-{4-[3-(2,5-dimethyl-1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone(Mixture of cis- and trans-isomers)

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 2,5-dimethylpyrrolidine as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.12 (6H,d,J=6.0 Hz), 1.35-1.40 (2H,m),1.80-1.86 (2H,m), 1.94-2.00 (2H,m), 2.57-2.66 (2H,m), 2.76 (2H,t,J=7.2Hz), 4.06 (2H,t,J=6.0 Hz), 7.02 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz),7.44 (1H,t,J=7.2 Hz), 7.65 (1H,d,J=8.0 Hz), 7.74 (1H,t,J=8.4 Hz), 8.25(1H,d,J=8.0 Hz)

Example 72-methyl-3-{4-[4-(1-piperidinyl)butoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 1,4-bromochlorobutane andpiperidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.53 (2H,m), 1.57-1.65 (4H,m),1.66-1.75 (2H,m), 1.97-2.06 (2H,m), 2.25 (3H,s), 2.36-2.50 (6H,m), 4.03(2H,t,J=6.4 Hz), 7.01 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.44(1H,t,J=8.0 Hz), 7.65 (1H,d,J=7.6 Hz), 7.74 (1H,t,J=8.0 Hz), 8.25(1H,d,J=8.0 Hz)

Example 83-{4-[3-(1-azepanyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and azepan as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.62-1.70 (8H,m), 2.25 (3H,s), 2.73(4H,brs), 4.08 (2H,t,J=6.2 Hz), 7.03 (2H,d,J=8.4 Hz), 7.12 (2H,d,J=8.4Hz), 7.44 (1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.8 Hz), 7.74 (1H,t,J=8.0 Hz),8.25 (1H,d,J=8.0 Hz)

Example 93-{4-[3-(1-azocanyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochlQropropane and azocan as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.57-1.63 (8H,m), 2.26 (3H,s), 2.56(4H,brs), 4.08 (2H,t,J=6.2 Hz), 7.03 (2H,d,J=8.4 Hz), 7.12 (2H,d,J=8.4Hz), 7.44 (1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.8 Hz), 7.74 (1H,t,J=8.0 Hz),8.25 (1H, d, J=8.0 Hz)

Example 102-methyl-3-{4-[3-(2-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 2-methylpiperidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.14 (3H,d,J=5.5 Hz), 1.36 (1H,brs), 1.36(1H,brs), 2.03 (1H,brs), 2.26 (3H,s), 2.42 (1H,brs), 2.60 (1H,brs), 2.93(1H,brs), 4.08 (2H,t,J=6.2 Hz), 7.03 (2H,d,J=8.4 Hz), 7.12 (2H,d,J=8.4Hz), 7.44 (1H,t,J=8.0 Hz), 7.65 (1H,d, J=8.8 Hz), 7.74 (1H,t,J=8.0 Hz),8.25 (1H,d,J=8.0 Hz)

Example 112-methyl-3-{4-[3-(4-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 4-methylpiperidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.93 (3H,d,J=6.6 Hz), 1.25-1.30 (1H,m), 1.36(1H,brs), 1.62-1.65 (1H,m), 1.92-2.03 (1H,m), 2.25 (3H,s), 2.49-2.51(1H,m), 2.90-2.93 (1H,m), 4.06 (2H,t,J=6.2 Hz), 7.02 (2H,d,J=6.6 Hz),7.12 (2H,d,J=6.6 Hz), 7.46 (1H,t,J=6.5 Hz), 7.65 (1H,d,J=7.7 Hz), 7.76(1H,t,J=8.4 Hz), 8.26 (1H,d, J=8.4 Hz)

Example 123-(4-(3-[([2R,6S)-2,6-dimethyl-1-piperidinyl]propoxy}phenyl)-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and (2R,6S)-2,6-dimethylpiperidine as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.18 (6H,d,J=6.6 Hz), 1.36 (2H,brs),1.58-1.68 (2H,m), 1.943 (1H,brs), 2.25 (3H,s), 2.54 (2H,brs), 3.00(2H,m), 3.99 (2H,t,J=5.8 Hz), 7.00 (2H,d,J=5.9 Hz), 7.12 (2H,d,J=5.9Hz), 7.43 (1H,t,J=6.6 Hz), 7.64 (1H,d,J=8.0 Hz), 7.76 (1H,t,J=8.4 Hz),8.23 (1H, d, J=8.0 Hz)

Example 132-methyl-3-{4-[3-(3-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 3-methylpiperidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.87 (3H,d,J=6.6 Hz), 1.57-1.72 (2H,m), 1.88(1H,td,J=11.0, 2.9 Hz), 1.98-2.06 (2H,m), 2.24 (3H,s), 2.52 (2H,t,J=7.3Hz), 2.85-2.92 (2H,m), 7.02 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.43(1H,t,J=7.3 Hz), 7.64 (1H,d,J=8.0 Hz), 7.73 (1H,t,J=8.0 Hz), 8.23(1H,d,J=8.6 Hz)

Example 143-{4-[3-(3,5-dimethyl-1-piperidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic-acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 3,5-dimethylpiperidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.86 (6H,d,J=6.8 Hz), 1.49 (2H,t,J=10.8),1.70-1.72 (2H,m), 2.24 (3H,s), 2.53 (2H,t,J=7.2 Hz), 2.88-2.90 (2H,m),4.04 (2H,t,J=6.8 Hz), 7.00 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.42(1H,t,J=7.2 Hz), 7.63 (1H,d,J=7.2 Hz), 7.72 (1H,t,J=8.0 Hz), 8.23(1H,d,J=8.0 Hz)

Example 152-methyl-3-{3-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 3-aminophenol,1,3-bromochloropropane and piperidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.39-1.47 (2H,m), 1.54-1.62 (4H,m),1.94-2.02 (2H,m), 2.28 (3H,s), 2.36-2.43 (4H,brs), 2.46 (2H,t,J=7.2 Hz),3.98-4.06 (2H,m), 6.77 (1H,s), 6.81 (1H,d,J=8.0 Hz), 7.01 (1H,d,J=8.4Hz), 7.397.47 (2H,m), 7.65 (1H,d,J=8.0 Hz), 7.75 (1H,t,J=8.0 Hz), 8.25(1H,d,J=8.4 Hz)

Example 163-{3-bromo-4-[3-(1-piperidinyl)propoxy]phenyl}-2-ethyl-4(3H)-quinazolinone(1) Manufacture of 2-bromo-1-(3-chloropropoxy)-4-nitrobenzene

4-amino-2-bromophenol (2.0 g, 9.17 mmol), 1,3-bromochloropropane (907μL, 9.17 mmol) and potassium carbonate (1.90 g, 13.8 mmol) were mixed indimethylformamide (8 mL), and stirred at 80° C. for 17 hours. Ethylacetate was added, the mixture washed with 1N sodium hydroxide aqueoussolution and distilled water in that order, and the organic phase wasdried with anhydrous sodium sulfate. The product was purified by silicagel column chromatography (hexane/ethyl acetate=9/1-7/3), and the targetsubstance (1.3 g, 48%) was thus obtained. 4-amino-2-bromophenol wasmanufactured by the method described in the literature (J. Org. Chem.,Vol. 62, 1997, p. 4504).

(2) Manufacture of 3-bromo-4-(3-chloropropoxy)aniline

2-bromo-1-(3-chloropropoxy)-4-nitrobenzene (1.3 g), ammonium chloride(1.3 g) and iron (1.3 g) were added to a mixed solvent of methanol (8mL) and distilled water (4 mL), and the mixture was heated under refluxfor 2 hours. The reaction mixture was filtered through cerite, and thefiltrate was concentrated. The residue was dissolved in ethyl acetate,and washed with distilled water and saturated brine. The organic phasewas dried with anhydrous sodium sulfate, concentrated and dried toobtain the target substance (0.92 g).

(3) Manufacture of3-[3-bromo-4-(3-chloropropoxy)phenyl]-2-ethyl-4(3H)-quinazolinone

3-bromo-4-(3-chloropropoxy)aniline (0.92 g, 4.92 mmol) and2-ethyl-4H-3,1-benzoxadin-4-one (0.87 g, 4.92 mmol) were dissolved indimethylformamide (3 mL), and stirred at 140° C. for 5 hours. Ethylacetate and distilled water were added, and the mixture extracted withethyl acetate and dried with anhydrous sodium sulfate. Methanol wasadded to the residue, and insoluble matter was filtered off. Thefiltrate was concentrated, the product purified by silica gel columnchromatography, (hexane/ethyl acetate=80/20-75/25), and the targetsubstance (416 mg, 20%) was thus obtained.

(4) Manufacture of3-{3-bromo-4-[3-(1-piperidinyl)propoxy]phenyl}-2-ethyl-4(3H)-quinazolinone

3-[3-bromo-4-(3-chloropropoxy)phenyl]-2-ethyl-4(3H)-quinazolinone (70mg) was dissolved in piperidine (1 mL), and stirred at 80° C. for 5hours. The reaction solution was diluted with diethyl ether, andinsoluble matter was filtered off. The filtrate was concentrated, driedunder vacuum, and the title compound (80 mg, 99%) was thus obtained as alight yellow solid.

¹HNMR (400 MHz,CDCl₃,δppm): 1.23 (3H,t,J=7.6 Hz), 1.43-1.53 (2H,m),1.54-1.66 (4H,m), 2.03-2.12 (2H,m), 2.39-2.52 (6H,m), 2.54-2.60 (2H,m),4.13-4.18 (2H,m), 7.04 (1H,d,J=8.4 Hz), 7.15 (1H,dd,J=2.8, 8.4 Hz),7.44-7.48 (2H,m), 7.71 (1H,d,J=8.0 Hz), 7.77 (1H,t,J=7.2 Hz), 8.26 (1H,d, J=8.0 Hz

Example 172-methyl-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-4(3H)-quinazolinone

2-methyl-3-(4-hydroxyphenyl)-4-(3H)quinazolinone synthesized accordingto Example 1-(1) and -(2) (100 mg, 0.40 mmol), 2-(1-piperidinyl)ethanol(89 mg, 0.50 mmol) and triphenylphosphine (125 mg, 0.50 mmol) weredissolved in dry tetrahydrofuran (2 mL) and cooled on an ice bath.Diethylazodicarboxylate (75 uL, 0.50 mmol) was dripped in at 0° C. andstirred at room temperature for 48 hours. The solvent was distilled offunder reduced pressure, ether was added, the solid precipitate wasfiltered off and the filtrate was concentrated. The residue was purifiedby silica gel column chromatography (chloroform/methanol=30/1) and thetitle compound (124 mg, 0.86%) was obtained as a light brown oilysubstance.

¹HNMR (400 MHz,CDCl₃,δppm): 1.77-1.83 (4H, m), 2.01-2.08 (2H,m), 2.25(3H,s), 2.51-2.59 (4H,m), 2.64 (2H,t,J=7.2 Hz), 4.08 (2H,t,J=6.4 Hz),7.03 (2H,d,J=9.2 Hz), 7.13 (2H,d,J=9.2 Hz), 7.44 (1H,t,J=8.0 Hz), 7.65(1H,d,J=8.0 Hz), 7.74 (1H,t,J=6.8 Hz), 8.25 (1H,d,J=8.0 Hz)

Example 182,5-dimethyl-3-{4-(3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone(1) Manufacture of 1-[3-(4-nitrophenoxy)propyl]piperidine

3-piperidin-1-yl-propan-1-ol (3.66 g, 25.6 mmol), 4-nitrophenol (2.96 g,21.3 mmol) and triphenylphosphine (6.71 g, 25.6 mmol) were dissolved indry tetrahydrofuran in a current of nitrogen, and cooled on the icebath. Diisopropyl azodicarboxylate (5.0 mL, 25.6 mmol) was dripped in,and stirred at room temperature for 40 hours. The reaction liquid wasconcentrated, diethyl ether was added, and the solid precipitate wasfiltered off. The filtrate was concentrated, the product purified bysilica gel column chromatography (chloroform/methanol=100/0-95/5), andthe target substance (3.49 g, 62%) was thus obtained as a light yellowoily residue.

1-[3-(4-nitrophenoxy)propyl]piperidine was also manufactured by thefollowing method.

Sodium hydride (2.8 g) was precipitated in dimethylformamide (20 mL) ina current of nitrogen, and 3-piperidin-1-yl-propan-1-ol (5.0 g, 34.9mmol) was slowly added on the ice bath. After 1 hour stirring at roomtemperature, 1-fluoro-4-nitrobenzene (4.92 g, 34.9 mmol) was added, andthe mixture stirred at room temperature for 15 hours. Distilled waterand ethyl acetate were added, the mixture extracted with ethyl acetate,and dried with anhydrous sodium sulfate. After concentration, theresidue was purified by silica gel column chromatography(chloroform/methanol=10/0-9/1), and the target substance (7.56 g, 82%)was thus obtained as a light yellow oily residue.

(2) Manufacture of 4-[(3-(1-piperidinyl)propoxy]aniline

1-[3-(4-nitrophenoxy)propyl]piperidine was dissolved in methanol, andthe target compound was obtained by catalytic reduction using apalladium charcoal catalyst in a current of hydrogen.

(3) Manufacture of2,5-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

2,5-dimethyl-4H-3,1-benzoxadin-4-one (100 mg, 0.57 mmol) and4-[(3-(1-piperidinyl)propoxy]aniline (134 mg, 0.57 mmol) were dissolvedin acetic acid (3 mL), and stirred at 130° C. for 10 hours. The solventwas distilled off under reduced pressure, and ethyl acetate and 1Nsodium hydroxide aqueous solution were added. The mixture was extractedwith ethyl acetate, and the organic phase was dried with anhydroussodium sulfate. After purification by silica gel column chromatography(chloroform/methanol=20/1), the title compound (76 mg, 34%) was obtainedas colorless crystals by recrystallization (ether/heptane).2,5-dimethyl-4H-3,1-benzoxadin-4-one was manufactured according to themethod of Example 1-(1), using 2-amino-6-methylbenzoic acid and aceticanhydride as starting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.41-1.50 (2H,m), 1.57-1.64 (4H,m),1.97-2.04 (2H,m), 2.22 (3H,s), 2.37-2.45 (4H,brs), 2.50 (2H,t,J=7.2 Hz),2.81 (3H,s), 4.05 (2H,t,J=6.4 Hz), 7.02 (2H,d,J=9.2 Hz), 7.12(2H,d,J=9.2 Hz), 7.19 (1H,d,J=7.6 Hz), 7.48 (1H,d,J=7.6 Hz), 7.57(1H,t,J=8.0 Hz)

NMR data for 4-[3-(1-piperidinyl)propoxy]aniline hydrochloride used formanufacturing the compound of this example is shown below.

¹HNMR (400 MHz,CDCl₃/CD₃OD=5/1,δppm): 1.40-1.49 (1H,m), 1.86-1.95(3H,m), 2.14-2.24 (2H,m), 2.32-2.38 (2H,m), 2.68-2.75 (2H,m), 3.17-3.21(2H,m), 3.62-3.57 (2H,m), 4.01 (2H,t,J=5.6 Hz), 6.76 (2H,d,J=8.8 Hz),6.85 (2H,d,J=8.8 Hz)

The compound of Example 19-62 can be manufactured by same method as thatof Example 18, a method based thereon or a combination of these with aconventional method, using the corresponding anthranilic acid, acidanhydride and 4-[3-(1-piperidinyl)propoxy]aniline,4-[3-(1-pyrrolidinyl)propoxy]aniline or5-amino-2-[3-(1-piperidinyl)propoxy]pyrimidine as starting materials.

Example 193-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-propyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, butyric anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.88 (3H,t,J=7.2 Hz), 1.41-1.52 (2H,m),1.55-1.62 (4H,m), 1.65-1.78 (2H,m), 1.97-2.06 (2H,m), 2.37-2.46 (6H,m),2.5.0 (2H,t,J=6.8 Hz), 4.06 (2H,t,J=6.8 Hz), 7.02 (2H,d,J=8.4 Hz), 7.12(2H,d,J=8.4 Hz), 7.43 (1H,t,J=8.0 Hz), 7.67 (1H,d,J=8.4 Hz), 7.73(1H,t,J=8.0 Hz), 8.24 (1H,d, J=8.0 Hz)

Example 203-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-trifluoromethyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, anhydrous trifluoroacetic acid and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.53 (2H,m), 1.59-1.64 (4H,m),2.00-2.08 (2H,m), 2.38-2.49 (4H,brs), 2.52 (2H,t,J=7.2 Hz), 4.06(2H,t,J=6.8 Hz), 7.00 (2H,d,J=8.8 Hz), 7.17 (2H,d,J=8.4 Hz), 7.60-7.65(1H,m), 7.84-7.89 (2H,m), 8.31 (1H,d,J=7.2 Hz)

Example 212-isopropyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, anhydrous isobutyl acid and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.21 (6H,d,J=6.4 Hz), 1.41-1.53 (2H,m),1.57-1.64 (4H,m), 1.97-2.06 (2H,m), 2.38-2.49 (4H,brs), 2.51 (2H,t,J=7.2Hz), 2.72-2.79 (1H,m), 4.06 (2H,t,J=6.4 Hz), 7.01 (2H,d,J=8.8 Hz), 7.12(2H,d,J=8.8 Hz), 7.41 (1H,t,J=7.6 Hz), 7.67-7.75 (2H,m), 8.23 (1H,d,J=8.0 Hz)

Example 222,6-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-5-methylbenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.53 (2H,m), 1.57-1.64 (4H,m),1.97-2.06 (2H,m), 2.23 (3H,s),2.38-2.49 (4H,brs), 2.48 (3H,s), 2.49(2H,t,J=7.2 Hz), 4.05 (2H,t,J=6.0 Hz), 7.01 (2H,d,J=9.2 Hz), 7.12(2H,d,J=8.8 Hz), 7.55 (2H,s),8.03 (1H,s)

Example 237-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-4-chlorobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.53 (2H,m), 1.57-1.65 (4H,m),1.97-2.06 (2H,m), 2.24 (3H,s), 2.37-2.48 (4H,brs), 2.50 (2H,t,J=7.2 Hz),4.06 (2H,t,J=6.0 Hz), 7.01 (2H,d,J=9.2 Hz), 7.12 (2H,d,J=9.2 Hz), 7.38(1H,dd,J=2.4, 8.4 Hz), 7.64 (1H,d,J=2.4 Hz), 8.16 (1H, d, J=8.8 Hz)

Example 242,8-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-3-methylbenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.51 (2H,m), 1.56-1.65 (4H,m),1.97-2.04 (2H,m), 2.26 (3H,s), 2.37-2.48 (4H,brs), 2.49 (2H,t,J=6.8 Hz),2.63 (3H,s), 4.05 (2H,t,J=6.4 Hz), 7.01 (2H,d,J=8.8 Hz), 7.11(2H,d,J=8.8 Hz), 7.31 (1H,t,J=8.0 Hz), 7.58 (1H,d,J=7.2 Hz), 8.09(1H,d,J=8.4 Hz)

Example 252-ethyl-5-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-methylbenzoic acid, propionic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.20 (3H,t,J=7.6 Hz), 1.41-1.51 (2H,m),1.57-1.65 (4H,m), 1.97-2.04 (2H,m), 2.38-2.53 (8H,m), 2.81 (3H,s), 4.05(2H,t,J=6.4 Hz), 7.02 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.18(1H,d,J=6.4 Hz) 7.50-7.60 (2H,m)

Example 265-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:141-145° C.)by the method according to Example 18, using 2-amino-6-fluorobenzoicacid, acetic anhydride and 4-(3-piperidinyl)propoxyaniline as startingmaterials, followed by recrystallization (ethyl acetate/n-pentane).

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.51 (2H,m), 1.57-1.65 (4H,m),1.97-2.04 (2H,m), 2.24 (3H,s), 2.37-2.48 (4H,brs), 2.50 (2H,t, J=7.2Hz), 4.06 (2H,t,J=6.0 Hz), 7.01 (2H,d,J=8.8 Hz), 7.05-7.13 (1H,m), 7.11(2H,d,J=8.8 Hz), 7.44 (1H,d,J=8.4 Hz), 7.63-7.69 (1H,m)

Example 275-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-chlorobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.50 (2H,m), 1.57-1.64 (4H,m),1.97-2.04 (2H,m), 2.23 (3H,s), 2.37-2.45 (4H,brs), 2.48 (2H,t,J=7.2 Hz),4.05 (2H,t,J=6.4 Hz), 7.01 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.43(1H,dd,J=1.6, 8.0 Hz), 7.53-7.60 (2H,m)

Example 285-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 3,using 2-amino-6-methoxybenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.50 (2H,m), 1.57-1.64 (4H,m),1.97-2.04 (2H,m), 2.21 (3H,s), 2.37-2.45 (4H,brs), 2.49 (2H,t,J=7.2 Hz),3.94 (3H,s), 4.04 (2H,t,J=6.4 Hz), 6.85 (1H,d,J=8.4 Hz), 6.99(2H,d,J=8.8 Hz), 7.09 (2H,d,J=8.8 Hz), 7.21 (1H,d,J=8.4 Hz), 7.62(1H,t,J=8.0 Hz)

Example 295-hydroxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonetrifluoroacetate

The title compound was obtained by demethylating5-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized in Example 28 using boron tribromide.

¹HNMR (400 MHz,CDCl₃,δppm): 1.90-2.04 (6H,m), 2.33 (3H,s), 2.85-3.00(4H,m), 3.22-3.30 (2H,m), 3.71-3.79 (2H,m), 4.13 (2H, t, J=6.0 Hz), 6.94(1H, d, J=8.4 Hz), 7.03 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.22(1H, d, J=8.0 Hz), 7.68 (1H, t, J=8.0 Hz)

Example 302-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-trifluoromethylbenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.50 (2H, m), 1.57-1.64 (4H,m),1.97-2.04 (2H,m), 2.26 (3H,s), 2.37-2.45 (4H,brs), 2.48 (2H,t,J=7.2 Hz),4.04 (2H,t,J=6.0 Hz), 7.01 (2H,d,J=8.4 Hz), 7.11 (2H,d,J=8.8 Hz), 7.77(1H,t,J=8.0 Hz), 7.83-7.87 (2H,m)

Example 317-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-4-fluorobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.42-1.49 (2H,m), 1.57-1.64 (4H,m), 1.96-2.06(2H,m), 2.24 (3H,s), 2.37-2.46 (4H,brs), 2.49 (2H,t,J=7.2 Hz), 4.06(2H,t,J=6.4 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.16(1H,dd,J=2.4, 8.4 Hz), 7.29 (1H,dd,J=2.4, 9.6 Hz), 8.25 (1H,dd,J=6.0,8.8 Hz)

Example 326-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-5-fluorobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.41-1.49 (2H,m), 1.56-1.65 (4H,m), 1.96-2.06(2H,m), 2.24 (3H,s), 2.37-2.46 (4H,brs), 2.49 (2H,t,J=6.8 Hz), 4.06(2H,t,J=6.4 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.42-7.48(1H,m), 7.65 (1H,dd,J=4.8, 9.2 Hz), 7.87 (1H,dd,J=2.8, 8.4 Hz)

Example 336,7-difluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-4,5-difluorobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.49 (2H,m), 1.57-1.63 (4H,m),1.96-2.05 (2H,m), 2.23 (3H,s), 2.37-2.46 (4H,brs), 2.49 (2H,t,J=6.8 Hz),4.06 (2H,t,J=6.4 Hz), 7.03 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.42(1H,dd,J=7.2, 11.2 Hz), 7.99 (1H,dd,J=8.4, 10 Hz)

Example 346-bromo-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-5-bromobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.45 (2H,brs), 1.57-1.65 (4H,m), 1.98-2.03(2H,m), 2.23 (3H,s), 2.41-2.51 (6H,m), 4.06 (2H,t,J=6.4 Hz), 7.03(2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.52 (1H,d,J=8.8 Hz), 7.81(1H,dd,J=2.4, 8.8 Hz), 8.36 (1H,s)

Example 356-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-5-chlorobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.49 (2H,m), 1.56-1.63 (4H,m),1.97-2.05 (2H,m), 2.24 (3H,s), 2.37-2.45 (4H,brs), 2.49 (2H,t,J=6.8 Hz),4.06 (2H,t,J=6.4 Hz), 7.02 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.59(1H,d,J=9.2 Hz), 7.66 (1H,dd,J=2.8, 8.8 Hz), 8.20 (1H,d,J=2.4 Hz)

Example 366-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:136-138° C.)by the method according to Example 18, using 2-amino-5-methoxybenzoicacid, acetic anhydride and 4-(3-piperidinyl)propoxyaniline as startingmaterials, followed by recrystallization (ethyl acetate/diethylether/n-pentane).

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.49 (2H,m), 1.56-1.63 (4H,m),1.98-2.05 (2H,m), 2.22 (3H,s), 2.37-2.46 (4H,brs), 2.49 (2H,t,J=7.6 Hz),3.89 (3H,s), 4.06 (2H,t,J=6.0 Hz), 7.02 (2H,d,J=8.8 Hz), 7.11(2H,d,J=8.8 Hz), 7.33 (1H,dd,J=2.8, 8.8 Hz), 7.58 (1H,d,J=8.8 Hz), 7.61(1H,d,J=3.2 Hz)

Example 376,7-dimethoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-4,5-dimethoxybenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.49 (2H,m), 1.57-1.65 (4H,m),1.98-2.05 (2H,m), 2.22 (3H,s), 2.37-2.46 (4H,brs), 2.49 (2H,t,J=7.6 Hz),3.97 (3H,s), 4.00 (3H,s), 4.06 (2H,t,J=6.0 Hz), 7.02 (2H,d,J=8.8 Hz),7.11 (2H,d,J=8.8 Hz), 7.24 (1H,s), 7.56 (1H,s)

Example 388-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-3-chlorobenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.48 (2H, m), 1.57-1.63 (4H,m),1.97-2.04 (2H,m), 2.32 (3H,s), 2.37-2.45 (4H,brs), 2.49 (2H,t,J=7.6 Hz),4.06 (2H,t,J=6.4 Hz), 7.03 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.35(1H,t,J=7.6 Hz), 7.81 (1H,dd,J=1.2, 8.0 Hz), 8.17 (1H,dd,J=1.2, 8.0 Hz)

Example 398-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-3-methoxybenzoic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.48 (2H,m), 1.57-1.63 (4H,m),1.97-2.04 (2H,m), 2.31 (3H,s), 2.37-2.45 (4H,brs), 2.49 (2H,t,J=7.2 Hz),4.03 (3H,s), 4.05 (2H,t,J=6.4 Hz), 7.02 (2H,d,J=8.8 Hz), 7.11(2H,d,J=8.8 Hz), 7.19 (1H,dd,J=1.2, 8.0 Hz), 7.38 (1H,t,J=8.0 Hz), 7.83(1H,dd,J=1.2, 8.0 Hz)

Example 402-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}benzo[g]-quinazolin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 3-amino-2-naphthoic acid, acetic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.52 (2H,m), 1.57-1.64 (4H,m),1.98-2.06 (2H,m), 2.28 (3H,s), 2.38-2.46 (4H,brs), 2.50 (2H,t,J=7.2 Hz),4.07 (2H,t,J=6.8 Hz), 7.04 (2H,d,J=8.8 Hz), 7.17 (2H,d,J=8.8 Hz), 7.51(1H,t,J=7.6 Hz), 7.59 (1H,t,J=7.6 Hz), 7.97 (1H,d,J=8.4 Hz), 8.03(1H,d,J=8.0 Hz), 8.12 (1H,s),8.86 (1H,s)

Example 412,6-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone(1) Manufacture of 4-[3-(1-pyrrolidinyl)propoxy]aniline

The target compound was obtained by the method according to Example 18,using 3-pyrrolidin-1-yl-propan-1-ol, and 4-nitrophenol or1-fluoro-4-nitrobenzene as starting materials.

(2) Manufacture of2,6-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-5-methylbenzoic acid, acetic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.76-1.84 (4H,m), 2.00-2.09 (2H,m), 2.23(3H,s), 2.47 (3H,s), 2.50-2.58 (4H,m), 2.64 (2H,t,J=7.2 Hz), 4.08(2H,t,J=6.4 Hz), 7.02 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.55(2H,s), 8.03 (1H,s)

NMR data for 4-[3-(1-pyrrolidinyl)propoxy]aniline used for manufacturingthe compound of this example is shown below.

¹HNMR (400 MHz,CDCl₃,δppm): 1.77-1.80 (4H,m), 1.93-2.00 (2H,m),2.49-2.54 (4H,m), 2.60 (2H,t,J=7.6 Hz), 3.41 (2H,brs), 3.95 (2H,t,J=6.6Hz), 6.63 (2H,d,J=8.8 Hz), 6.74 (2H,d,J=9.3 Hz)

4-[3-(1-pyrrolidinyl)propoxy]aniline can also be obtained as4-[3-(1-pyrrolidinyl)propoxy]aniline ditosylate by treating with 2 Eq ofp-toluenesulfonic acid. NMR data for this tosyl salt is shown below.

1HNMR (DMSO-d6)δ: 1.81-1.90 (2H,m), 1.96-2.05 (2H,m), 2.06-2.13 (2H,m),2.29 (6H,s), 3.02-3.04 (2H,m), 3.28-3.30 (2H,m), 3.57-3.59 (2H,m), 4.05(2H,t,J=6.1 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (4H,d,J=7.8 Hz), 7.28(2H,d,J=8.8 Hz), 7.49 (4H,d,J=7.8 Hz), 9.49 (1H,brs), 9.73 (2H,brs)

Example 422-ethyl-5-methyl-3-{(4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-methylbenzoic acid, propionic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.20 (3H,t,J=7.2 Hz), 1.76-1.85 (4H,m),2.00-2.09 (2H,m), 2.43 (2H,q,J=7.6 Hz),2.50-2.59 (4H,m), 2.65(2H,t,J=7.2 Hz), 2.81 (3H,s), 4.07 (2H,t,J=6.0 Hz), 7.03 (2H,d,J=8.8Hz), 7.12 (2H,d,J=8.8 Hz), 7.18 (1H,d,J=6.8 Hz), 7.51-7.59 (2H,m)

Example 435-fluoro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-fluorobenzoic acid, acetic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.77-1.83 (4H,m), 2.00-2.08 (2H,m), 2.23(3H,s), 2.51-2.56 (4H,m), 2.64 (2H,t,J=7.2 Hz), 4.08 (2H,t,J=6.4 Hz),7.03 (2H,d,J=8.8 Hz), 7.02-7.11 (1H,m), 7.12 (2H,d,J=8.8 Hz), 7.43(1H,d,J=8.0 Hz), 7.63-7.68 (1H,m)

Example 442-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:137-140° C.)by the method according to Example 18, using2-amino-6-trifluoromethylbenzoic acid, acetic anhydride and4-[(3-(1-pyrrolidinyl)propoxy]aniline as starting materials, followed byrecrystallization (ethyl acetate/n-pentane).

¹HNMR (400 MHz,CDCl₃,δppm): 1.77-1.83 (4H,m), 2.00-2.08 (2H,m), 2.26(3H,s), 2.51-2.57 (4H,m), 2.63 (2H,t,J=7.2 Hz), 4.07 (2H,t,J=6.8 Hz),7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.79 (1H,t,J=7.6 Hz),7.82-7.88 (2H,m)

Example 455-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-chlorobenzoic acid, acetic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.77-1.84 (4H,m), 2.00-2.08 (2H,m), 2.22(3H,s), 2.51-2.56 (4H,m), 2.64 (2H,t,J=6.8 Hz), 4.07 (2H,t,J=6.4 Hz),7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.43 (1H,dd,J=2.0, 7.6 Hz),7.44-7.60 (2H,m)

Example 462-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, propionic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.21 (3H,t,J=7.2 Hz), 1.77-1.84 (4H,m),2.01-2.09 (2H,m), 2.46 (2H,q,J=7.2 Hz), 2.51-2.58 (4H,m), 2.65(2H,t,J=6.8 Hz),4.08 (2H,t,J=6.4 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12(2H,d,J=8.8 Hz), 7.43 (1H,t,J=8.0 Hz), 7.67-7.76 (2H,m), 8.24(1H,d,J=8.4 Hz)

Example 472,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:112-113° C.)by the method according to Example 18, using 2-amino-6-methylbenzoicacid, acetic anhydride and 4-[(3-(1-pyrrolidinyl)propoxy]aniline asstarting materials, followed by recrystallization (ethyl acetate/diethylether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.77-1.84 (4H,m), 2.01-2.09 (2H,m), 2.22(3H,s), 2.51-2.58 (4H,m), 2.63 (2H,t,J=7.2 Hz), 2.81 (3H,s), 4.07(2H,t,J=6.4 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.19(1H,d,J=7.6 Hz), 7.48 (1H,d,J=8.0 Hz), 7.57 (1H, t, J=8.0 Hz)

Example 482-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 2-amino-nicotinic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃:CD₃OD=6:1,δppm): 1.42-1.53 (2H,m), 1.59-1.67(4H,m), 2.00-2.07 (2H,m), 2.33 (3H,s), 2.41-2.48 (4H,brs), 2.53(2H,t,J=7.2 Hz), 4.06 (2H,t,J=6.4 Hz), 7.05 (2H,d,J=8.8 Hz), 7.13(2H,d,J=8.8 Hz), 7.43 (1H,dd,J=4.4, 7.6 Hz), 8.58 (1H,dd,J=2.4, 7.6 Hz),8.95 (1H, dd, J=2.0, 4.8 Hz)

Example 492-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 2-aminonicotinic acid, acetic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.76-1.84 (4H,m), 2.00-2.10 (2H,m), 2.34(3H,s), 2.50-2.59 (4H,m), 2.65 (2H,t,J=6.8 Hz), 4.08 (2H,t,J=6.4 Hz),7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.39 (1H,dd,J=4.8, 8.8 Hz),8.56 (1H,dd,J=2.4, 8.4 Hz), 8.96 (1H,dd,J=2.4, 4.4 Hz)

Example 506-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-chloroisonicotinic acid, acetic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.5-amino-2-chloroisonicotinic acid was manufactured according to themethod described in the literature (J. Chem. Soc. Perkin Trans. 1, 1996,p. 2221).

¹HNMR (400 MHz,CD₃OD, δppm): 2.08-2.16 (4H,brs), 2.24-2.32 (5H,m),3.37-3.48 (6H,m), 4.21 (2H,t,J=5.6 Hz), 7.16 (2H,d,J=9.2 Hz), 7.31(2H,d,J=9.2 Hz), 8.03 (1H,s), 8.83 (1H,s)

Example 512-methyl-3-[4-[3-(1-piperidinyl)propoxy]phenylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 63 in ethyl acetate using a palladium charcoalcatalyst in the presence of triethylamine.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.41-1.50 (2H,m), 1.57-1.64 (4H,m),1.98-2.05 (2H,m), 2.29 (3H,s),2.39-2.45 (4H,brs), 2.50 (2H,t,J=7.2 Hz),4.06 (2H,t,J=6.4 Hz), 7.05 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 8.01(1H,d,J=5.2 Hz), 8.65 (1H,d,J=5.2 Hz), 9.10 (1H,s)

Example 522-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 4-aminonicotinic acid, acetic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CD₃OD, δppm): 2.23-2.33 (4H,m), 2.23-2.33 (5H,m),3.36-3.49 (6H,brt,J=8.0 Hz), 4.20 (2H,t,J=6.0 Hz), 7.14 (2H,d,J=8.8 Hz),7.30 (2H,d,J=8.8 Hz), 7.57 (1H,dd,J=0.8, 6.0 Hz), 8.78 (1H,d,J=5.6 Hz),9.28 (1H,d,J=0.8 Hz)

Example 532-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 4-aminonicotinic acid, acetic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.40-1.49 (2H,m), 1.53-1.66 (4H,m),1.97-2.05 (2H,m), 2.29 (3H,s),2.35-2.45 (4H,brs), 2.50 (2H,t,J=6.8 Hz),4.07 (2H,t,J=6.4 Hz), 7.04 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.47(1H,dd,J=0.8, 5.2 Hz), 8.82 (1H,d,J=5.6 Hz), 9.45 (1H,d,J=0.8 Hz)

Example 542-methyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone(1) Manufacture of 5-nitro-2-(3-piperidin-1-yl-propoxy)pyrimidine

2-chloro-5-nitropyrimidine (300 mg, 1.88 mmol),3-piperidin-1-yl-propan-1-ol (323 mg, 2.26 mmol) and cesium carbonate(725 mg, 3.76 mmol) were mixed in dry dimethylformamide (5 mL), andstirred for 2 days at room temperature. The solvent was distilled offunder reduced pressure, ethyl acetate and 1N sodium hydroxide aqueoussolution were added, and the mixture extracted with ethyl acetate. Afterdrying with anhydrous sodium sulfate, the product was purified by silicagel column chromatography (chloroform/methanol=30/1), and the targetcompound (110 mg, 22%) was obtained as a light brown solid.2-chloro-5-nitropyrimidine was manufactured by the method described inthe literature (Heterocycles, 1984, Vol. 22, p. 79).

(2) Manufacture of 5-amino-2-(3-piperidin-1-yl-propoxy)pyrimidine

5-nitro-2-(3-piperidin-1-yl-propoxy)pyrimidine (100 mg, 0.38 mmol) wasdissolved in a mixed solvent of methanol (2 mL) and distilled water (2mL), sodium dithionite (Na2S204) (655 mg) was added, and the mixturestirred for 30 minutes at room temperature. The solvent was distilledoff under reduced pressure, methanol was added to the residue, and theprecipitate was filtered off. The filtrate was concentrated, and thetarget compound (60 mg, 68%) was obtained as a yellow oily residue.

(3) Manufacture of2-methyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, acetic anhydride and5-amino-2-[3-(1-piperidinyl)propoxy]pyrimidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.41-1.47 (2H,m), 1.57-1.64 (4H,m), 2.02-2.10(2H,m), 2.30 (3H,s),2.37-2.46 (4H,brs), 2.53 (2H,t, J=7.2 Hz), 4.49(2H,t,J=6.4 Hz), 7.49 (1H,dt,J=0.8, 7.6 Hz), 7.67 (1H,d,J=7.6 Hz), 7.79(1H,dt,J=1.6, 7.6 Hz), 8.24 (1H,dd,J=1.6, 8.0 Hz), 8.43 (2H,s)

Example 552,5-dimethyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-methylbenzoic acid, acetic anhydride and5-amino-2-(3-(1-piperidinyl)propoxy]pyrimidine as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.40-1.48 (2H,m), 1.57-1.64 (4H,m),2.02-2.10 (2H,m), 2.27 (3H,s), 2.37-2.47 (4H,brs), 2.49 (3H,s), 2.53(2H,t, J=7.2 Hz), 4.48 (2H,t,J=6.4 Hz), 7.55-7.62 (2H,m), 8.02 (1H,s),8.42 (2H,s)

Example 562-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 2-aminonicotinic acid, propionic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,CD₃OD, δppm) 1.30 (3H,t,J=7.2 Hz), 1.42-1.52(2H,brs), 1.59-1.67 (4H,m), 1.97-2.07 (2H,m), 2.47-2.58 (8H,m), 4.07(2H,t,J=6.4 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.39(1H,dd,J=4.8, 8.0 Hz), 8.57 (1H,dd,J=2.0, 7.6 Hz), 8.96 (1H,dd,J=2.4,4.8 Hz)

Example 576-chloro-2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-chloroisonicotinic acid, propionic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.23 (3H,t,J=7.2 Hz), 1.41-1.50 (2H,m),1.57-1.64 (4H,m), 1.98-2.05 (2H,m), 2.39-2.53 (8H,m), 4.07 (2H,t,J=6.4Hz), 7.05 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 8.06 (1H,s), 8.94(1H,s)

Example 586-chloro-2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-chloroisonicotinic acid, propionic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz, CDCl₃,δppm): 1.23 (3H,t,J=7.6 Hz), 1.79-1.86 (4H,m),2.01-2.11 (2H,m), 2.46 (2H,q,J=7.6 Hz), 2.50-2.62 (4H,brs), 2.67 (2H,t,J=6.8 Hz), 4.09 (2H,t,J=6.4 Hz), 7.05 (2H,d,J=8.8 Hz), 7.10 (2H,d,J=8.8Hz), 8.03 (1H,s), 8.91 (1H,s)

Example 592-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 57 using palladium charcoal as catalystin the presence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.24 (3H,t,J=7.2 Hz), 1.41-1.49 (2H,m),1.57-1.65 (4H,m), 1.98-2.06 (2H,m), 2.39-2.56 (8H,m), 4.07 (2H,t, J=6.4Hz), 7.03 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 8.00 (1H,dd,J=0.8, 4.8Hz), 8.64 (1H,dd,J=4.8 Hz), 9.13 (1H,d,J=0.8 Hz)

Example 602-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 58 using palladium charcoal as catalystin the presence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.24 (3H,t, J=7.2 Hz), 1.81-1.86 (4H,m),2.05-2.13 (2H,m), 2.48 (2H,q,J=7.2 Hz), 2.59-2.67 (4H,brs), 2.72(2H,t,J=7.2 Hz), 4.09 (2H,t,J=6.0 Hz), 7.03 (2H,d,J=8.8 Hz), 7.1(2H,d,J=8.8 Hz), 8.00 (1H,dd,J=0.8, 5.2 Hz), 8.64 (1H,dd,J=4.8 Hz), 9.13(1H,d,J=0.8 Hz)

Example 612-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 4-aminonicotinic acid, propionic anhydride and4-[3-(1-piperidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δ ppm): 1.23 (3H,t,J=7.6 Hz), 1.42-1.51 (2H,m),1.59-1.67 (4H,m), 2.00-2.09 (2H,m), 2.42-2.58 (8H,m), 4.08 (2H,t,J=6.4Hz), 7.05 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.53 (1H,d,J=6.0 Hz),8.84 (1H,d,J=5.6 Hz), 9.47 (1H,s)

Example 622-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 4-aminonicotinic acid, propionic anhydride and4-[3-(1-pyrrolidinyl)propoxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.23 (3H,t,J=7.2 Hz), 1.99-2.07 (4H,m),2.25-2.35 (2H,m), 2.48 (2H,q,J=7.6 Hz), 2.96-3.07 (4H,brs), 4.14(2H,t,J=6.0 Hz), 7.05 (2H,d,J=8.8 Hz), 7.15 (2H,d,J=8.8 Hz), 7.53(1H,d,J=5.6 Hz), 8.84 (1H,d,J=5.6 Hz), 9.47 (1H,s)

Example 636-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

Using 5-amino-4-carboxy-2-chloropyridine and acetic anhydride asstarting materials,6-chloro-2-methyl-3-(4-hydroxyphenyl)pyrido[3,4-d]pyrimidin-4(3H)-onesynthesized according to Example 1-(1) and -(2) (52 mg, 0.18 mmol),1-(3-bromopropyl)piperidine hydrobromide (78 mg, 0.27 mmol) andpotassium carbonate (100 mg, 0.72 mmol) were mixed in dimethylformamide(1 mL) and stirred at 80° C. for 1 hour. The solvent was distilled offunder reduced pressure, distilled water was added, and the mixture wasextracted with ethyl acetate. The organic phase was washed withdistilled water, and dried with anhydrous sodium sulfate. The titlecompound (45 mg, 60%) was obtained as colorless crystals by purifyingwith silica gel column chromatography (chloroform/methanol=30/1) andrecrystallizing (ethanol).

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.50 (2H,m), 1.57-1.64 (4H,m),1.98-2.05 (2H,m), 2.28 (3H,s),2.39-2.46 (4H,brs), 2.50 (2H,t,J=7.2 Hz),4.06 (2H,t,J=6.4 Hz), 7.04 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 8.04(1H,s), 8.88 (1H,s)

Example 64 3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by alkylating3-(4-hydroxyphenyl)-4(3H)quinazolinone and 1-(3-bromopropyl)piperidinehydrobromide according to Example 63. 3-(4-hydroxyphenyl)-4 (3H)quinazolinone was manufactured by the method described in the literature(Heterocycles, 1993, Vol. 35, p. 775).

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.50 (2H,m), 1.56-1.63 (4H,m),1.97-2.04 (2H,m), 2.38-2.45 (4H,brs), 2.49 (2H,t,J=7.2 Hz), 4.06(2H,t,J=6.8 Hz), 7.02 (2H,d, J=8.8 Hz), 7.29 (2H,d,J=8.8 Hz), 7.52(1H,t,J=8.0 Hz), 7.72-7.80 (2H,m), 8.09 (1H,s), 8.34 (1H,d,J=8.0 Hz)

Example 656-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone(1) Manufacture of6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

2-methyl-6-nitro-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized according to Example 1 (110 mg, 0.26 mmol) was dissolved inmethanol (3 mL), and the atmosphere in the system replaced by nitrogen.After adding 10% palladium charcoal (100 mg), the atmosphere wasreplaced by hydrogen, and the mixture stirred at room temperature for 1Hour. The catalyst was filtered off, and the filtrate was concentratedto dryness to obtain the target compound (91 mg, 89%) as a light yellowsolid.

(2) Manufacture of6-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone(228 mg, 0.58 mmol) were dissolved in a mixed solvent of drytetrahydrofuran (5 mL) and dry pyridine (1 mL), and coooled on an icebath. Acetyl chloride (68 mg, 0.87 mmol) was dripped in, and the mixturestirred at room temperature overnight. Ethyl acetate and 1N sodiumhydroxide aqueous solution were added, the mixture was extracted withethyl acetate, and the organic phase was dried with anhydrous sodiumsulfate. The product was purified by silica gel column chromatography(chloroform/methanol=20/1), and the title compound (156 mg, 62%) wasobtained as colorless crystals by recrystallization from diethylether/heptane.

¹HNMR (400 MHz,CDCl₃,δppm): 1.40-1.49 (2H,m), 1.52-1.65 (4H,m),1.97-2.07 (2H,m), 2.02 (3H,s), 2.23 (3H,s), 2.38-2.46 (4H,brs), 2.50(2H,t,J=7.2 Hz), 4.05 (2H,t,J=6.0 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12(2H,d,J=8.8 Hz), 7.64 (1H,d,J=8.8 Hz), 7.86-7.92 (1H,brs), 7.99(1H,d,J=2.8 Hz), 8.40 (1H,dd,J=2.0, 8.8 Hz)

The compound of Example 66-79 was obtained by condensation ofamino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith the corresponding acid chloride or carboxylic acid according to themethod of Example 65.

Example 666-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensing6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith butanoyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 0.99 (3H,t,J=7.6 Hz), 1.42-1.50 (2H,m),1.56-1.66 (4H,m), 1.68-1.78 (2H,m), 1.98-2.07 (2H,m), 2.23 (3H,s), 2.25(2H,t,J=7.6 Hz), 2.38-2.46 (2H,brs), 2.49 (2H,t,J=7.2 Hz), 4.05(2H,t,J=6.0 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.63(1H,d,J=8.8 Hz), 7.65 (1H,s), 7.97 (1H,d,J=2.4 Hz), 8.38 (1H,d,J=9.2 Hz)

Example 676-(hexanoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensing6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith hexanoyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 0.91 (3H,t,J=6.8 Hz), 1.29-1.40 (4H,m),1.41-1.49 (2H,m), 1.58-1.65 (4H,m), 1.66-1.78 (2H,m), 1.97-2.06 (2H,m),2.23 (3H,s), 2.28 (2H,t,J=7.6 Hz), 2.38-2.46 (4H,brs), 2.49 (2H,t,J=7.2Hz), 4.05 (2H,t,J=6.0 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz),7.63 (1H,d,J=8.8 Hz), 7.64 (1H,s), 7.97 (1H,d,J=2.8 Hz), 8.38(1H,dd,J=2.4, 8.4 Hz)

Example 686-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensing6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith benzoyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 1.40-1.49 (2H,m), 1.55-1.65 (4H,m),1.95-2.05 (2H,m), 2.24 (3H,s), 2.37-2.46 (4H,brs), 2.48 (2H,t,J=7.2 Hz),4.02 (2H,t,J=6.0 Hz), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.48(2H,t,J=7.6 Hz), 7.52-7.57 (1H,m), 7.70 (1H,d,J=8.8 Hz), 7.86(2H,d,J=7.6 Hz), 8.09 (1H,d,J=2.4 Hz), 8.15 (1H,brs), 8.48 (1H,dd,J=2.8,8.8 Hz)

Example 696-[(2-phenylacetyl)amino]2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith benziloyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 1.40-1.49 (2H,brs), 1.50-1.65 (4H,m),1.93-2.05 (2H,m), 2.21 (3H,s), 2.37-2.45 (4H,brs), 2.48 (2H,t,J=7.2 Hz),3.60 (2H,s), 3.97 (2H,brt), 6.97 (2H,d,J=8.0 Hz), 7.10 (2H,d,J=8.0 Hz),7.20-7.41 (5H,m), 7.61 (1H,d,J=9.2 Hz), 7.69 (1H,s), 7.89 (1H,s), 8.33(1H,d,J=8.8 Hz)

Example 706-(2-naphthoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensing6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith 2-naphthoyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃, δppm): 1.40-1.49 (2H,m), 1.55-1.65 (4H,m),1.92-2.00 (2H,m), 2.23 (3H,s), 2.37-2.50 (6H,m), 3.93 (2H,t,J=6.0 Hz),6.93 (2H,d,J=8.8 Hz), 7.09 (2H,d,J=8.8 Hz), 7.53-7.62 (2H,m), 7.72(1H,d,J=8.8 Hz), 7.86-7.95 (4H,m), 8.17 (1H,d,J=2.4 Hz), 8.39 (1H,s),8.44 (1H,s), 8.55 (1H,dd,J=2.4, 9.2 Hz)

Example 712-methyl-6-[(methylsulfonyl)amino]-3-{3-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith mesyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 1.49-1.60 (2H,m), 1.71-1.80 (4H,m),2.12-2.20 (2H,m), 2.24 (3H,s),2.62-2.70 (4H,brs), 2.73 (2H,t,J=7.6 Hz),2.97 (3H,s), 4.07 (2H,t,J=6.0 Hz), 7.01 (2H,d,J=8.8 Hz), 7.11(2H,d,J=8.8 Hz), 7.63 (1H,d,J=8.4 Hz), 7.74 (1H,dd,J=2.4, 8.4 Hz), 8.02(1H,d,J=2.4 Hz)

Example 722-methyl-6-[(methylsulfonyl)amino]-3-{3-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of6-amino-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith mesyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 2.01-2.09 (4H,m), 2.24 (3H,s), 2.25-2.34(2H,m), 3.01 (3H,s), 3.05-3.18 (6H,m), 4.13 (2H,t,J=6.0 Hz), 7.03(2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.65 (1H,d,J=8.8 Hz), 7.77(1H,dd,J=2.4, 8.4 Hz), 7.91 (1H,d,J=2.4 Hz)

Example 737-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensing7-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith acetyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 1.53-1.40 (2H,m), 1.69-1.59 (4H,m),2.10-2.00 (2H,m), 2.21 (3H,s), 2.22 (3H,s), 2.55-2.46 (4H,m), 2.58(2H,t,J=7.3 Hz), 4.04 (2H,t,J=6.2 Hz), 6.99 (2H,d,J=8.8 Hz), 7.11(2H,d,J=8.8 Hz), 7.58 (2H,m), 7.82 (1H,brs), 8.16 (1H,d,J=8.8 Hz)

Example 747-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of7-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith butanoyl chloride according to the method of Example 65.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.52-1.40 (2H,m), 1.66-1.58 (4H,m), 1.77(2H,m), 2.00 (2H,t,J=10.0 Hz), 2.21 (3H,s), 2.38 (2H,t,J=6.6 Hz), 2.52(2H,brs), 2.55 (2H,t,J=12.2 Hz), 4.03 (2H,t,J=6.2 Hz) 6.99 (2H,d,J=8.8Hz), 7.11 (2H,d,J=8.8 Hz), 7.54 (1H,s), 7.61 (1H,dd,J=8.4, 1.8 Hz), 7.79(1H,d,J=2.2 Hz), 1.01 (3H,t,J=7.3 Hz), 8.15 (1H,d,J=8.8 Hz)

Example 757-(hexanoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of7-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith hexanoyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CDCl₃,δppm): 0.91 (3H,t,J=7.0 Hz), 1.41-1.29 (4H, m),1.53-1.41 (2H,m), 1.68-1.57 (4H,m), 1.81-1.68 (2H,m),2.08-1.97 (2H,m),2.22 (3H,s), 2.39 (2H,t,J=10.0 Hz), 2.47 (4H,m), 2.56 (2H,t,J=10.0 Hz),4.04 (2H,t,J=6.2 Hz), 7.00 (2H,d, J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.63(1H,d,J=8.8 Hz), 7.72 (1H,brs), 7.80 (1H,brs), 8.15 (1H,d,J=8.8 Hz)

Example 767-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of7-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith benzoyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CD₃OD, δppm): 1.57-1.47 (2H,m), 1.72-1.63 (4H,m),2.12-2.02 (2H,m), 2.24 (3H,s),2.63-2.54 (2H,m), 2.66 (2H,t,J=10.8 Hz),3.32-3.28 (8H,m), 4.11 (2H,t,J=5.9 Hz), 7.10 (2H,d,J=8.8 Hz), 7.25(2H,d,J=8.8 Hz), 7.52 (2H,t,J=7.3 Hz), 7.60 (1H,t,J=7.3 Hz), 7.79(1H,dd,J=8.8, 2.2 Hz), 7.96 (2H,d,J=7.3 Hz), 8.14 (1H,d,J=8.8 Hz), 8.27(1H,d,J=2.2 Hz)

Example 777-[(2-phenylacetyl)amino]2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of7-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith benziloyl chloride according to the method of Example 65.

¹HNMR (400 MHZ,CD₃OD, δppm) 1.62-1.47 (2H,m), 1.78-1.63 (4H,m),2.16-2.02 (2H,m), 2.21 (3H,s), 2.67-2.56 (4H,m), 2.70 (2H,t,J=10.0 Hz),3.74 (2H,s), 4.11 (2H,t,J=5.9 Hz), 7.09 (2H,d,J=8.8 Hz), 7.42-7.20(8H,m), 7.63 (1H,d,J=8.8 Hz), 8.09 (2H,d,J=8.1 Hz)

Example 787-(2-naphthoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by condensation of7-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith 2-naphthoyl chloride according to the method of Example 65.

¹HNMR (400 MHz,CD₃OD, δppm): 1.74-1.61 (2H,m), 1.90-1.77 (4H,m), 2.26(3H,s), 3.24-3.05 (4H,m), 3.34-3.27 (2H,m), 4.19 (2H,t,J=5.5 Hz), 7.13(2H,d,J=8.8 Hz), 7.30 (2H,d,J=8.8 Hz), 7.68-7.57 (2H,m),7.88-7.84(2H,m), 7.96 (1H,d,J=8.8 Hz), 8.08-8.00 (3H,m), 8.17 (1H,d,J=8.8 Hz),8.34 (1H,d,J=2.2 Hz), 8.56 (1H,s)

Example 796-[acetyl(methyl)amino]-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by treating6-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized in Example 65 with sodium hydride in dimethylformamide, andmethylating with methyl iodide.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.50 (2H,m), 1.58-1.66 (4H,m),1.98-2.08 (2H,m), 2.27 (3H,s),2.40-2.50 (4H,brs), 2.53 (2H,t,J=7.6 Hz),3.31 (3H,s), 4.07 (2H,t,J=6.4 Hz), 7.02 (2H,d,J=8.4 Hz), 7.12(2H,d,J=8.4 Hz), 7.55 (1H,d,J=8.4 Hz), 7.70 (1H,d,J=8.4 Hz), 8.05 (1H,s)

Example 802-methyl-6-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized in Example 34 (100 mg, 0.25 mmol) and phenylboronic acid (40mg, 0.32 mmol) were dissolved in dimethoxyethane (1 mL), and theatmosphere in the system was replaced by nitrogen. 2M sodium carbonateaqueous solution (0.3 mL) and palladium tetrakis (triphenylphosphine)complex (10 mg, 0.012 mmol) were added, and stirred at 80° C. for 3hours. Ethyl acetate and distilled water were added to the reactionmixture to perform an ethyl acetate extraction. The organic phase waswashed with saturated brine and dried with anhydrous sodium sulfate. Theproduct was purified by silica gel column chromatography(chloroform/methanol=20/1), and the target substance (61 mg, 61%) wasobtained as a colorless solid. ¹HNMR (400 MHz,CDCl₃,δppm): 1.45(2H,brs), 1.58-1.63 (4H,m), 2.00-2.04 (2H,m), 2.27 (3H,s), 2.42(4H,brs), 2.50 (2H,t,J=7.2 Hz), 4.07 (2H,t,J=6.4 Hz), 7.04 (2H,d,J=8.8Hz), 7.15 (2H,d,J=8.8 Hz), 7.36 (1H,t,J=7.6 Hz), 7.46 (2H,t,J=7.6 Hz),7.67 (2H,d,J=7.2 Hz), 7.72 (1H,d,J=8.4 Hz), 7.98 (1H,d,J=2.0 Hz), 8.46(1H,s)

Example 812-methyl-6-(4-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by Suzuki coupling of2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith 4-methylphenylboronic acid according to the method of Example 80.

¹HNMR (400 MHz,CDCl₃,δppm): 1.46 (2H,brs), 1.59-1.63 (4H,m), 2.01-2.04(2H,m), 2.28 (3H,s), 2.41 (7H,brs), 2.49-2.53 (2H,m), 4.08 (2H,t,J=6.0Hz), 7.05 (2H,d,J=8.8 Hz), 7.16 (2H,d,J=8.8 Hz), 7.27 (2H,d,J=8.0 Hz),7.58 (2H,d,J=8.0 HZ), 7.71 (1H,d,J=8.8 Hz), 7.97-8.00 (1H,m),8.46 (1H,s)

Example 822-methyl-6-(3-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by Suzuki coupling of2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith 3-methylphenylboronic acid according to the method of Example 80.

¹HNMR (400 MHz,CDCl₃,δppm): 1.47 (2H,brs), 1.59-1.64 (4H,m), 2.02-2.06(2H,m), 2.28 (3H,s), 2.44 (7H,m), 2.52 (2H,t,J=7.2 Hz), 4.08 (2H,t,J=6.4Hz), 7.05 (2H,d,J=7.2 Hz), 7.15-7.20 (3H,m), 7.35 (1H,t,J=7.2 Hz),7.47-7.50 (2H,m), 7.72 (1H,dd,J=2.0, 8.8 Hz), 7.98-8.01 (1H,m), 8.46(1H,s)

Example 832-methyl-6-(2-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by Suzuki coupling of2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith 2-methylphenylboronic acid according to the method of Example 80.

¹HNMR (400 MHz,CDCl₃,δppm): 1.46 (2H,brs), 1.59-1.64 (4H,m), 2.01-2.05(2H,m), 2.29 (3H,s), 2.30 (3H,s), 2.43 (4H,brs), 2.51 (2H,t,J=7.2 Hz),4.07 (2H,t,J=6.8 Hz), 7.04 (2H,d,J=8.8 Hz), 7.16 (2H,d,J=8.8 Hz),7.24-7.30 (4H,m), 7.71 (2H,brs), 8.21 (1H,brs)

Example 842-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(3-pyridyl)-4(3H)-quinazolinone

The title compound was obtained by Suzuki coupling of2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith 3-pyridylboronic acid according to the method of Example 80.

¹HNMR (400 MHz,CD₃OD, δppm): 1.51-1.53 (2H,m), 1.63-1.67 (4H,m),2.04-2.08 (2H,m), 2.28 (3H,s), 2.59 (4H,brs), 2.61-2.63 (2H,m), 4.11(2H,t,J=6.4 Hz), 7.11 (2H,d,J=9.2 Hz), 7.28 (2H,d,J=8.8 Hz), 7.53-7.757(1H,m), 7.79 (1H,d,J=8.4 Hz), 8.14-8.21 (4H,m), 8.45 (1H,d,J=2.4 Hz),8.55 (1H,dd,J=1.8, 5.0 Hz), 8.89 (1H,dd,J=0.6, 2.2 Hz)

Example 852-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(4-pyridyl)-4(3H)-quinazolinone

The title compound was obtained by Suzuki coupling of2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonewith 4-pyridylboronic acid according to the method of Example 80.

¹HNMR (400 MHz,CD₃OD, δppm): 1.51-1.52 (2H,m), 1.63-1.68 (4H,m)2.04-2.08 (2H,m), 2.28 (3H,s) 2.54 (4H,brs), 2.58-2.62 (2H,m), 4.11(2H,t,J=6.0 Hz), 7.11 (2H,d,J=8.4 Hz), 7.28 (2H,d,J=8.8 Hz), 7.78-7.81(3H,m), 8.23 (1H,dd,J=2.4, 8.4 Hz), 8.54 (1H,s), 8.61 (2H,d,J=6.4 Hz)

Example 862-methyl-5-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

5-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized in Example 27 (100 mg, 0.24 mmol), phenylboric acid (90 mg,0.73 mmol) and cesium carbonate (480 mg, 1.45 mmol) were mixed in1,4-dioxane (1 mL), and the atmosphere in the system was replaced bynitrogen. Pd₂ (dba)₃ (15 mg, 0.012 mmol) and tri-t-butylphosphine (10mg, 0.036 mmol) were added, and stirred at 100° C. for 12 hours.Distilled water was added to the reaction mixture, and the mixtureextracted with chloroform. The organic phase was washed by saturatedbrine, and dried with anhydrous sodium sulfate. The product was purifiedby thin layer silica gel chromatography, and the title compound (20 mg,18%) was obtained as a colorless solid.

¹HNMR (400 MHz,CDCl₃,δppm): 1.44 (2H,brs), 1.56-1.62 (4H,m), 1.95-1.99(2H,m), 2.23 (3H,s), 2.40 (4H,brs), 2.46 (2H,t,J=6.8 Hz), 3.99(2H,t,J=6.8 Hz), 6.94 (2H,d,J=8.8 Hz), 7.06 (2H,d,J=8.8 Hz), 7.23-7.33(6H,m), 7.66-7.73 (2H,m)

Example 872-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl)-6-(2-pyridyl)-4(3H)-quinazolinone

6-bromo-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized in Example 34 (100 mg, 0.25 mmol) and2-(tributylstannyl)pyridine (90 mg, 0.25 mmol) were dissolved in toluene(1 mL), and the atmosphere in the system was replaced by nitrogen.Palladium tetrakis(triphenylphosphine) complex (30 mg, 0.025 mmol) wasadded, and stirred at 120° C. for 12 hours. Insoluble matter wasfiltered off through cerite, chloroform was added to the filtrate, theorganic phase was washed with distilled water, and dried with anhydroussodium sulfate. The product was purified by silica gel columnchromatography (chloroform/methanol=9/1), and the target substance (20mg, 20%) was obtained as a colorless solid.

¹HNMR (400 MHz,CD₃OD, δppm): 1.50-1.51 (2H,m), 1.62-1.67 (4H,m),2.03-2.08 (2H,m), 2.28 (3H,s), 2.51 (4H,brs), 2.56-2.60 (2H,m), 4.11(2H,t,J=5.6 Hz), 7.11 (2H,d,J=9.2 Hz), 7.28 (2H,d,J=9.2 Hz), 7.37-7.40(1H,m), 7.76 (1H,d,J=8.8 Hz), 7.89-7.98 (4H,m), 8.45 (1H,dd,J=2.0, 8.4Hz), 8.63-8.65 (2H,m)

Example 88 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone (1) Manufacture of3-{4-[(1-t-butoxycarbonyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

2-methyl-3-(4-hydroxyphenyl)-4 (3H)quinazolinone synthesized accordingto Example 1-(1) and -(2) (1.0 g, 3.96 mmol),N-(t-butoxycarbonyl)-4-piperidinol (956 mg, 4.75 mmol) andtriphenylphosphine (1.56 g, 5.94 mmol) were dissolved in drytetrahydrofuran (2 mL) in a current of nitrogen, and cooled on an icebath. Diethylazodicarboxylate (1.17 mL, 5.94 mmol) was dripped in at 0°C., and stirred at room temperature for 48 hours. The solvent wasdistilled off under reduced pressure, ether was added, the solidprecipitate was filtered off, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=7/3), and the target substance (1.1 g, 64%) was obtained as alight brown solid.

(2) Manufacture of2-methyl-3-[4-(4-piperidinyloxy)phenyl]-4(3H)-quinazolinone

3-{4-[(1-t-butoxycarbonyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone(1.1 g, 2.53 mmol) was dissolved in chloroform (10 mL), trifluoroaceticacid (10 mL) was added and the mixture stirred at room temperature for30 minutes. The solvent was distilled off under reduced pressure, ethylacetate and 2N sodium hydroxide aqueous solution were added, the mixturewas extracted with ethyl acetate, and the organic phase was dried withanhydrous sodium sulfate. The sodium sulfate was filtered off, and thefiltrate was concentrated and dried to obtain the target substance (0.83g, 98%) as a lavender-colored solid.

¹HNMR (400 MHz,CDCl₃,δppm): 1.67-1.81 (2H,m), 2.01-2.10 (2H,m), 2.26(3H,s),2.72-2.80 (2H,m),3.13-3.20 (2H,m), 4.40-4.47 (1H,m), 7.03(2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.0 Hz), 7.65(1H,d,J=7.6 Hz), 7.74 (1H,t,J=7.6 Hz), 8.25 (1H,d,J=8.0 Hz)

(3) Manufacture of3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

2-methyl-3-{4-(4-piperidinyloxy-)phenyl}-4(3H)-quinazolinone (370 mg,1.10 mmol) and cyclobutanone (155 mg, 2.20 mmol) were dissolved in a0.5M methanol solution (6 mL) of zinc(II) chloride and sodiumcyanoborohydride, and stirred at room temperature for 1 Hour. Thesolvent was distilled off under reduced pressure, ethyl acetate anddistilled water were added, the mixture was extracted with ethylacetate, and the organic phase washed with distilled water. After dryingwith anhydrous sodium sulfate, the product was purified by silica gelcolumn chromatography (chloroform/methanol=30/1), and the title compound(165 mg, 39%) was obtained as a colorless solid.

¹HNMR (400 MHz,CDCl₃,δppm) 1.63-1.76 (2H,m), 1.84-1.95 (4H,m), 1.99-2.10(4H,m), 2.14-2.23 (2H,m), 2.26 (3H,s), 2.59-2.67 (2H,m), 2.70-2.79(1H,m), 4.33-4.41 (1H,m), 7.01 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.0 Hz),7.65 (1H,d,J=8.4 Hz), 7.74 (1H,t,J=7.6 Hz), 8.24 (1H,d, J=7.6 Hz)

Example 893-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by performing a reductive aminationaccording to the method of Example 88-(3), using2-methyl-3-[4-(4-piperidinyloxy)phenyl]-4(3H)-quinazolinone,N-Boc-4-piperidinol and cyclopentanone as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.25-1.48 (2H,m), 1.52-1.61 (2H,m),1.66-1.73 (2H,m), 1.83-1.93 (4H,m), 2.01-2.12 (2H,m), 2.25 (3H,s),2.32-2.40 (2H,m), 2.49-2.58 (1H,m), 2.79-2.95 (2H,m), 4.33-4.41 (1H,m),7.03 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=7.2 Hz), 7.65(1H,d,J=7.6 Hz), 7.74 (1H,t,J=7.2 Hz), 8.25 (1H,d,J=7.6 Hz)

Example 903-{4-(1-cyclohexyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by performing a reductive aminationaccording to the method of Example 88-(3), using2-methyl-3-[4-(4-piperidinyloxy)phenyl]-4(3H)-quinazolinone,N-Boc-4-piperidinol and cyclohexanone as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.18-1.30 (6H,m), 1.78-1.90 (6H,m),2.01-2.08 (2H,m), 2.26 (3H,s), 2.27-2.36 (1H,m), 2.42-2.51 (2H,m),2.81-2.89 (2H,m), 4.30-4.38 (1H,m), 7.03 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.0 Hz), 7.74 (1H,t,J=8.0Hz), 8.25 (1H,d,J=8.0 Hz)

Example 91 3-{4-(1-isopropyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by performing a reductive aminationaccording to the method of Example 88-(3), using2-methyl-3-[4-(4-piperidinyloxy)phenyl]-4(3H)-quinazolinone,N-Boc-4-piperidinol and acetone as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.07 (6H,d,J=6.4 Hz), 1.82-1.92 (2H,m),2.02-2.11 (2H,m), 2.26 (3H,s),2.37-2.46 (2H,m), 2.72-2.84 (3H,m),4.31-4.40 (1H,m), 7.03 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.44(1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.0 Hz), 7.74 (1H,t,J=8.0 Hz), 8.25 (1H,d, J=8.0 Hz)

Example 923-{4-(1-ethyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone

2-methyl-3-[4-(4-piperidinyloxy)phenyl]-4(3H)-quinazolinone (50 mg, 0.15mmol), ethyl iodide (23 mg, 0.15 mmol) and potassium carbonate (0.30mmol) were mixed in dimethylformamide (1 mL), and stirred at roomtemperature for 1 hour. The solvent was distilled off under reducedpressure, ethyl acetate and 1N sodium hydroxide aqueous solution wasadded, and the mixture was extracted with ethyl acetate. The organicphase was washed with distilled water, dried with anhydrous sodiumsulfate, and the product was purified by silica gel columnchromatography (chloroform/methanol=30/1) to obtain the title compound(25 mg, 46%) as a colorless solid.

¹HNMR (400 MHz,CDCl₃,δppm): 1.12 (3H,t,J=6.8 Hz), 1.83-1.95 (2H,m),2.02-2.10 (2H,m), 2.26 (3H,s),2.26-2.39 (2H,m), 2.45 (2H,q,J=7.2 Hz),2.72-2.81 (2H,m), 4.35-4.43 (1H,m), 7.03 (2H,d,J=8.8 Hz), 7.13(2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.0 Hz), 7.74(1H,t,J=8.0 Hz), 8.25 (1H,d,J=8.0 Hz)

Example 933-{4-(1-butyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by N-alkylation, using2-methyl-3-[4-(4-piperidinyloxy-)phenyl}-4(3H)-quinazolinone and butyliodide according to Example 92.

¹HNMR (400 MHz,CDCl₃,δppm): 0.93 (3H,t,J=7.2 Hz), 1.28-1.39 (2H,m),1.46-1.54 (2H,m), 1.83-1.93 (2H,m), 2.01-2.10 (2H,m), 2.26 (3H,s),2.26-2.39 (4H,m), 2.72-2.81 (2H,m), 4.33-4.41 (1H,m), 7.03 (2H,d,J=8.8Hz), 7.13 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.0 Hz), 7.65 (1H,d,J=8.0 Hz),7.74 (1H,t,J=8.0 Hz), 8.25 (1H,d,J=8.0 Hz)

Example 943-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone (1) Manufacture of4-(4-nitrophenoxy)piperidine

N-Boc-4-piperidinol (10 g, 50 mmol), 4-nitrophenol (7.0 g, 50 mmol) andtriphenylphosphine (15.7 g, 60 mmol) were dissolved in drytetrahydrofuran (150 mL), and cooled on the ice bath. Diisopropylazodicarboxylate (11.8 mL, 60 mmol) was added slowly, and stirred for 2days at room temperature. The solvent was distilled off under reducedpressure, diethyl ether was added, and the solid precipitate wasfiltered off. The filtrate was concentrated and the product was purifiedby silica gel column chromatography (hexane/ethyl acetate=6/1).Trifluoroacetic acid was added to the obtained residue and stirred atroom temperature for 1 hour. After distillation under reduced pressure,1N sodium hydroxide aqueous solution was added, and the mixtureextracted with ethyl acetate. After drying with anhydrous sodiumsulfate, the product was concentrated and dried to obtain the targetsubstance (6.75 g, 61%).

(2) Manufacture of 1-cyclopentyl-4-(4-nitrophenoxy)piperidine

4-(4-nitrophenoxy)piperidine (1.03 g, 4.65 mmol) and cyclopentanone (783mg, 9.31 mmol) were dissolved in a 0.5M methanol solution (20 mL) ofzinc(II) chloride and sodium cyanoborohydride, and stirred at roomtemperature for 10 hours. The solvent was distilled off under reducedpressure, ethyl acetate and 1N sodium hydroxide aqueous solution wereadded, the mixture was extracted with ethyl acetate, and the organicphase washed with distilled water. After drying with anhydrous sodiumsulfate, the product was concentrated, and the target compound (1.31 g,96%) was thereby obtained as a light brown solid.

(3) Manufacture of 4-[(1-cyclopentylpiperidin-4-yl)oxy]aniline

1-cyclopentyl-4-(4-nitrophenoxy)piperidine (1.30 g) was dissolved inmethanol, and the target compound (1.0 g, 86%) was obtained as a lightbrown solid by catalytic reduction using a palladium charcoal catalyst.

(4) Manufacture of3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone

2-methyl-5-trifluoromethyl-4H-3,1-benzoxadin-4-one (71 mg, 0.31 mmol)and 4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline (80 mg, 0.31 mmol) weredissolved in acetic acid (0.5 mL), and stirred at 130 degrees for 6hours. The solvent was distilled off under reduced pressure, and ethylacetate and 1N sodium hydroxide-aqueous solution were added. The mixturewas extracted with ethyl acetate, and the organic phase was dried withanhydrous sodium sulfate. The product was purified by silica gel columnchromatography (chloroform/methanol=20/1), and the title compound (88mg, 61%) was thus obtained as a light brown solid.2-methyl-5-trifluoromethyl-4H-3,1-benzoxadin-4-one was manufactured bythe method according to Example 1-(1), using2-amino-6-trifluoromethylbenzoic acid and acetic anhydride as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.38-1.49 (2H,m), 1.51-1.62 (2H,m),1.65-1.76 (2H,m), 1.82-1.94 (4H,m), 2.00-2.09 (2H,m), 2.26 (3H,s),2.32-2.42 (2H,m), 2.48-2.58 (1H,m), 2.76-2.86 (2H,m), 4.32-4.40 (1H,m),7.02 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.78 (1H,t,J=8.0 Hz),7.83-7.88 (2H,m)

NMR data for 4-[(1-cyclopentylpiperidin-4-yl)oxy]aniline used formanufacturing the compound of this example is shown below.

¹HNMR (400 MHz,CDCl₃,δppm): 1.36-1.45 (2H,m), 1.49-1.58 (2H,m),1.64-1.99 (10H,m), 2.24-2.31 (2H,m), 2.45-2.54 (1H,m), 2.80 (2H,brs),3.43 (2H,brs), 4.12 (1H,s), 6.63 (2H,d,J=8.8 Hz), 6.76 (2H,d,J=8.8 HZ)

The product of Example 95-115 can be manufactured by an identical methodto that of Example 94, a method based thereon or a combination of thesewith a conventional method, using the corresponding anthranilic acid,acid anhydride and 4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline or4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline as starting materials.

Example 953-{4-(1-cyclopentyl-4-piperidinyloxy-)phenyl}-2,5-dimethyl-4(3H)-quinazolinone

The title compound was obtained by cyclizing, using2,5-dimethyl-4H-3,1-benzoxazin-4-one and4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline, according to the method ofExample 94.

¹HNMR (400 MHz,CDCl₃,δppm): 1.37-1.50 (2H,m), 1.54-1.61 (2H,m),1.64-1.78 (4H,m), 1.82-1.96 (4H,m), 2.00-2.10 (2H,m), 2.22 (3H,s),2.32-2.42 (2H,m), 2.49-2.59 (1H,m), 2.81 (3H,s), 4.32-4.41 (1H,m), 7.03(2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.19 (1H,d,J=7.2 Hz), 7.48(1H,d,J=7.6 Hz), 7.57 (1H,t,J=8.0 Hz)

Example 967-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by cyclizing, using7-chloro-2-methyl-4H-3,1-benzoxazin-4-one and4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline according to the method ofExample 94.

¹HNMR (400 MHz,CDCl₃,δppm): 1.37-1.49 (2H,m), 1.50-1.63 (2H,m),1.65-1.76 (2H,m), 1.82-1.94 (4H,m), 2.00-2.10 (2H,m), 2.25 (3H,s),2.30-2.41 (2H,m), 2.48-2.58 (1H,m), 2.77-2.87 (2H,m), 4.33-4.41 (1H,m),7.02 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.38 (1H,dd,J=2.4, 8.4 Hz),7.64 (1H,d,J=2.4 Hz), 8.16 (1H,d,J=8.4 Hz)

Example 973-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2,6-dimethyl-4(3H)-quinazolinone

The title compound was obtained by cyclizing, using2,6-dimethyl-4H-3,1-benzoxazin-4-one and4-[(1-cyclopentyl-4-piperidinyl) oxy] aniline according to the method ofExample 94.

¹HNMR (400 MHz,CDCl₃,δppm): 1.38-1.49 (2H,m), 1.50-1.63 (2H,m),1.65-1.76 (2H,m), 1.84-1.95 (4H,m),2.00-2.11 (2H,m), 2.23 (3H,s),2.31-2.42 (2H,m), 2.48 (3H,s), 2.48-2.58 (1H,m), 2.78-2.86 (2H,m),4.33-4.41 (1H,m), 7.02 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.55(2H,s),8.02 (1H,s)

Example 986-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy-one]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by cyclizing, using6-chloro-2-methyl-4H-3,1-benzoxazin-4-one and 4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline according to the method of Example 94.

¹HNMR (400 MHz,CDCl₃,δppm): 1.37-1.48 (2H,m), 1.50-1.62 (2H,m),1.65-1.77 (2H,m), 1.84-1.94 (4H,m),2.00-2.10 (2H,m), 2.24 (3H,s),2.30-2.41 (2H,m), 2.48-2.59 (1H,m), 2.78-2.87 (2H,m), 4.33-4.41 (1H,m),7.02 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.58 (1H,d,J=8.8 Hz), 7.68(1H,dd,J=2.4, 8.8 Hz), 8.19 (1H,d, J=2.8 Hz)

Example 993-{4-[(1-cyclopentyl-4-piperidinyl)oxy-one]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone

The title compound was obtained by cyclizing, using6-methoxy-2-methyl-4H-3,1-benzoxazin-4-one and4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline according to the method ofExample 94.

¹HNMR (400 MHz,CDCl₃,δppm): 1.37-1.48 (2H,m), 1.50-1.62 (2H,m),1.65-1.77 (2H,m), 1.84-1.94 (4H,m),2.00-2.10 (2H,m), 2.23 (3H,s),2.30-2.41 (2H,m), 2.49-2.58 (1H,m), 2.78-2.87 (2H,m), 3.89 (3H,s),4.33-4.41 (1H,m), 7.02 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.33(1H,dd,J=2.8, 8.8 Hz), 7.58 (1H,d,J=8.8 Hz), 7.61 (1H,d,J=3.2 Hz)

Example 1003-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was obtained by cyclizing, using2-methyl-4H-pyrido[2,3-d](1,3]oxadin-4-one and4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline according to the method ofExample 94.

¹HNMR (400 MHz,CDCl₃,δppm): 1.37-1.48 (2H,m), 1.49-1.63 (2H,m),1.64-1.74 (2H,m), 1.83-1.93 (4H,m),2.00-2.10 (2H,m), 2.34(3H,s),2.29-2.40 (2H,m),2.49-2.58 (1H,m), 2.78-2.88 (2H,m), 4.33-4.41(1H,m), 7.04 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.39 (1H,dd,J=4.0,7.6 Hz), 8.56 (1H,dd,J=2.4, 7.6 Hz), 8.96 (1H,dd,J=2.4, 4.8 Hz)

Example 1013-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained as a white solid (m.p.:140-143° C.) bycyclizing, using 2-methyl-4H-pyrido[4,3-d][1,3]oxazin-4-one and4-[(1-cyclopentyl-4-piperidinyl)oxy]aniline according to the method ofExample 94, followed by recrystallization (ethyl acetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.39-1.49 (2H,m), 1.49-1.63 (2H,m),1.64-1.78 (2H,m), 1.83-1.95 (4H,m), 2.00-2.12 (2H,m), 2.29 (3H,s),2.32-2.45 (2H,m), 2.50-2.61 (1H,m), 2.78-2.88 (2H,m), 4.34-4.41 (1H,m),7.05 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.47 (1H,d,J=5.6 Hz), 8.82(1H,d,J=5.6 Hz), 9.45 (1H,s)

Example 1026-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by cyclizing, using6-chloro-2-methyl-4H-pyrido[3,4-d][1,3]oxadin-4-one and4-[(1-cyclopentyl-4-piperidinyl)oxy] aniline according to the method ofExample 94.

¹HNMR (400 MHz,CDCl₃,δppm): 1.37-1.48 (2H,m), 1.50-1.62 (2H,m),1.65-1.76 (2H,m), 1.83-1.94 (4H,m),2.00-2.10 (2H,m), 2.28 (3H,s),2.32-2.42 (2H,m), 2.48-2.58 (1H,m), 2.78-2.87 (2H,m),4.33-4.41 (1H,m),7.04 (2H,d,J=8.8 Hz), 7.10 (2H,d,J=8.8 Hz), 8.03 (1H,s), 8.88 (1H,s)

Example 1033-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-3-(4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 102 using palladium charcoal as catalyst in thepresence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.40-1.64 (4H,m), 1.65-1.79 (2H,m),1.84-1.99 (4H,m), 2.01-2.10 (2H,m), 2.29 (3H,s), 2.37-2.45 (2H,m),2.49-2.64 (1H,m), 2.78-2.87 (2H,m), 4.33-4.47 (1H,m), 7.03 (2H,d,J=8.8Hz), 7.12 (2H,d,J=8.8 Hz), 8.00 (1H,d,J=5.2 Hz), 8.65 (1H,d,J=5.2 Hz),9.10 (1H,s)

Example 1043-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone(1) Manufacture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline

The target compound was obtained as a light brown solid by the methodaccording to Example 94, using 4-(4-nitrophenoxy)piperidine synthesizedin Example 94 and cyclobutanone as starting materials.4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline monotosylate can also beprepared by treating the obtained4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline with one equivalent ofp-toluenesulfonic acid.

(2) Manufacture of3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:142-143° C.)by the method according to Example 94, using 2-amino-6-methylbenzoicacid, acetic anhydride and 4-[(1-cyclobutyl-4-pyridinyl)oxy]aniline asstarting materials, followed by recrystallization (ethyl acetate).

¹HNMR (400 MHz,CDCl₃,δppm): 1.63-1.75 (2H,m), 1.82-1.96 (4H,m),1.99-2.10 (4H,m), 2.13-2.22 (2H,m), 2.22 (3H,s), 2.58-2.67 (2H,m),2.69-2.79 (1H,m), 2.81 (3H,s), 4.33-4.40 (1H,m), 7.02 (2H,d,J=8.8 Hz),7.11 (2H,d,J=8.8 Hz), 7.19 (1H,d,J=8.0 Hz), 7.48 (1H,d,J=8.0 Hz), 7.57(1H,t,J=8.0 Hz)

NMR data for 4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline used formanufacturing the compound of this example is shown below.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.62-2.10 (12H,m), 2.58-2.65 (2H,m),2.67-2.76 (1H,m), 3.43 (1H,brs), 4.15-4.10 (1H,m), 6.62 (2H,d,J=8.8 Hz),6.76 (2H,d,J=8.8 Hz)

NMR data for 4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline monotosylate isshown below.

¹HNMR (400 MHz,CDCl₃/CD₃OD=4/1,δppm): 1.68-1.79 (1H,m), 1.81-1.90(1H,m), 2.09-2.15 (2H,m), 2.19-2.27 (2H,m), 2.34-2.43 (5H,m), 2.52-2.61(2H,m), 2.86-2.93 (2H,m), 3.34-3.44 (3H,m), 4.52 (1H,brs), 6.70-6.75(4H,m), 7.21 (2H,d,J=7.8 Hz), 7.79 (2H,d,J=7.8 Hz)

Example 1053-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone

The title compound was synthesized as a light yellow solid(m.p.:153-156° C.) by the method according to Example 94, using2-amino-6-methoxybenzoic acid, acetic anhydride and4-(1-cyclobutyl-4-piperidinyl)oxyaniline as starting materials, followedby recrystallization (ethyl acetate/diethyl ether/n-heptane).

¹HNMR (400 MHz,CDCl₃,δppm): 1.63-1.77 (2H,m), 1.82-1.96 (4H,m),1.98-2.09 (4H,m), 2.12-2.23 (2H,m), 2.21 (3H,s), 2.58-2.67 (2H,m),2.69-2.79 (1H,m), 3.94 (3H,s), 4.33-4.40 (1H,m), 6.85 (1H,d,J=8.8 Hz),6.99 (2H,d,J=8.8 Hz), 7.08 (2H,d,J=8.8 Hz), 7.21 (1H,d,J=8.0 Hz), 7.62(1H,t,J=8.0 Hz)

Example 1063-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:132-134° C.)by the method according to Example 94, using2-amino-6-trifluoromethylbenzoic acid, acetic anhydride and4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline as starting materials,followed by recrystallization (ethyl acetate).

¹HNMR (400 MHz,CDCl₃,δppm): 1.63-1.77 (2H,m), 1.82-1.96 (4H,m),1.98-2.09 (4H,m), 2.13-2.23 (2H,m), 2.26 (3H,s), 2.58-2.66 (2H,m),2.70-2.79 (1H,m), 4.33-4.40 (1H,m), 7.01 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.77 (1H,d,J=8.0 Hz), 7.82-7.88 (2H,m)

Example 1075-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-chlorobenzoic acid, acetic anhydride and4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.63-1.77 (2H,m), 1.82-1.96 (4H,m),1.99-2.09 (4H,m), 2.13-2.23 (2H,m), 2.23 (3H,s), 2.58-2.66 (2H,m),2.69-2.79 (1H,m), 4.33-4.40 (1H,m), 7.00 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.43 (1H,dd,J=1.6, 7.2 Hz), 7.52-7.61 (2H,m)

Example 1083-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 4-aminonicotinic acid, acetic anhydride and4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.63-1.77 (2H,m), 1.82-1.96 (4H,m), 1.99-2.11(4H,m), 2.14-2.24 (2H,m), 2.29 (3H,s), 2.60-2.68 (2H,m), 2.70-2.80(1H,m), 4.33-4.41 (1H,m), 7.03 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz),7.47 (1H,d,J=5.2 Hz), 8.82 (1H,d,J=5.2 Hz), 9.45 (1H,s)

Example 1093-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was synthesized as a white solid (m.p.:186-189° C.)by the method according to Example 94, using 4-aminonicotinic acid,propionic anhydride and 4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline asstarting materials, followed by recrystallization (ethyl acetate/diethylether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.23 (3H,t,J=7.2 Hz), 1.64-1.78 (2H,m),1.83-1.97 (4H,m), 2.00-2.11 (4H,m), 2.14-2.23 (2H,m), 2.49 (2H,q,J=7.2Hz), 2.60-2.68 (2H,m), 2.70-2.80 (1H,m), 4.36-4.42 (1H,m), 7.06(2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8 Hz), 7.53 (1H,d,J=6.0 Hz), 8.84(1H,d,J=6.0 Hz), 9.47 (1H,s)

Example 1103-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 2-aminonicotinic acid, acetic anhydride and4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.63-1.77 (2H,m), 1.82-1.95 (4H,m),1.99-2.11 (4H,m), 2.15-2.23 (2H,m), 2.34 (3H,s), 2.60-2.68 (2H,m),2.70-2.80 (1H,m), 4.33-4.41 (1H,m), 7.03 (2H,d,J=8.8 Hz), 7.12(2H,d,J=8.8 Hz), 7.39 (1H,dd,J=4.4, 8.0 Hz), 8.56 (1H,dd,J=2.0, 7.6 Hz),8.96 (1H,dd,J=2.4, 4.8 Hz)

Example 1113-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was synthesized as a white solid (m.p.:146-148° C.)by the method according to Example 94, using 2-aminonicotinic acid,propionic anhydride and 4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline,followed by recrystallization (ethyl acetate/diethyl ether).

¹HNMR (400 MHZ,CDCl₃,δppm): 1.30 (3H,t,J=7.2 Hz), 1.65-1.75 (2H,m),1.82-1.95 (4H,m), 1.99-2.11 (4H,m), 2.14-2.23 (2H,m), 2.51 (2H,q,J=7.2Hz),2.60-2.68 (2H,m), 2.70-2.79 (1H,m), 4.34-4.41 (1H,m), 7.02(2H,d,J=8.8 Hz), 7.10 (2H,d,J=8.8 Hz), 7.39 (1H,dd,J=4.4, 8.8 Hz), 8.57(1H,dd,J=2.0, 8.0 Hz), 8.96 (1H,dd,J=2.4, 4.8 Hz)

Example 1126-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 5-amino-2-chloroisonicotinic acid, acetic anhydride and4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.63-1.77 (2H,m), 1.82-1.96 (4H,m), 1.99-2.11(4H,m), 2.14-2.22 (2H,m), 2.28 (3H,s), 2.60-2.68 (2H,m), 2.70-2.79(1H,m), 4.33-4.41 (1H,m), 7.02 (2H,d,J=8.8 Hz), 7.10 (2H,d,J=8.8 Hz),8.03 (1H,s), 8.87 (1H,s)

Example 1136-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 5-amino-2-chloroisonicotinic acid, propionic anhydride and4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.23 (3H,t,J=7.6 Hz), 1.62-1.75 (2H,m),1.82-1.95 (4H,m), 1.99-2.10 (4H,m), 2.10-2.24 (2H,m), 2.46 (2H,q,J=7.2Hz), 2.60-2.68 (2H,m), 2.70-2.79 (1H,m), 4.34-4.41 (1H,m), 7.02(2H,d,J=8.8 Hz), 7.08 (2H,d,J=8.8 Hz), 8.03 (1H,s), 8.91 (1H,s)

Example 1143-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained as a light yellow solid (m.p.:169-171°C.) by catalytic reduction of6-chloro-3-{4-[(cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidine-4(3H)-onesynthesized in Example 112 in ethyl acetate using palladium charcoal ascatalyst in the presence of triethylamine, followed by recrystallization(ethyl acetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm) 1.63-1.77 (2H,m), 1.82-1.95 (4H,m), 1.99-2.11(4H,m), 2.15-2.23 (2H,m), 2.29 (3H,s), 2.60-2.69 (2H,m), 2.73-2.83(1H,m), 4.36-4.43 (1H,m), 7.03 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz),8.01 (1H,dd,J=0.8, 5.6 Hz), 8.65 (1H,d,J=5.2 Hz), 9.09 (1H,d,J=0.8 Hz)

Example 1153-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 113 using palladium charcoal as catalystin the presence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.23 (3H,t,J=7.2 Hz), 1.65-1.75 (2H,m),1.82-1.96 (4H,m), 2.00-2.11 (4H,m), 2.14-2.23 (2H,m), 2.48 (2H,q,J=7.6Hz), 2.60-2.68 (2H,m), 2.70-2.79 (1H,m), 4.33-4.42 (1H,m), 7.02(2H,d,J=8.8 Hz), 7.10 (2H,d,J=8.8 Hz), 8.00 (1H,dd,J=0.8, 5.2 Hz), 8.64(1H,d,J=5.2 Hz), 9.13 (1H,d,J=0.8 Hz)

Example 1162-phenyl-3-[4-(3-piperidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone (1)Manufacture of 2-phenyl-4H-3,1-benzoxazin-4-one

Anthranilic acid (1.0 g, 7.29 mmol) was dissolved in pyridine (10 mL),benzoyl chloride (1.13 g, 8.02 mmol) was slowly added on an ice bath,and stirred at 50° C. overnight. The solvent was distilled off underreduced pressure, the residue was dissolved in dry methylene chloride(20 mL), oxalyl chloride (925 mg, 7.29 mmol) and a catalytic amount ofdimethylformamide were added on an ice bath, and stirred at roomtemperature for 4 hours. Saturated sodium hydrogen carbonate aqueoussolution was added, the mixture was extracted with methylene chloride,and the organic phase was dried with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, the residue was washedby diethyl ether/heptane, and the target substance (1.13 g, 69%) wasobtained as a light yellow solid.

(2) Manufacture of2-phenyl-3-[4-(3-piperidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by cyclizing2-phenyl-4H-3,1-benzoxazin-4-one and 4-(3-piperidin-1-ylpropoxy)anilineaccording to Example 18-(2).

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.50 (2H,m), 1.54-1.62 (4H,m),1.90-1.99 (2H,m), 2.34-2.42 (4H,brs), 2.44 (2H,t,J=7.2 Hz), 3.94(2H,t,J=6.4 Hz), 6.79 (2H,d,J=8.8 Hz), 7.01 (2H,d,J=8.8 Hz),7.19-7.25(3H,m), 7.30-7.34 (2H,m), 7.48-7.53 (1H,m), 7.77-7.80 (2H,m), 8.33(1H,d,J=8.4 Hz)

Example 117cis-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinoneandtrans-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone(1) Manufacture of 1,4-dioxaspiro[4.5]decan-8-ol

1,4-dioxaspiro[4.5]decan-8-one (1.0 g, 6.40 mmol) was dissolved inmethanol (10 mL), sodium borohydride (242 mg, 6.40 mmol) was slowlyadded, and stirred at room temperature for 5 minutes. The mixture wascooled on an ice bath, 10% hydrochloric acid aqueous solution and sodiumchloride were added, and the mixture extracted with ethyl acetate. Theorganic phase was washed with saturated brine, and dried by anhydroussodium sulfate. The sodium sulfate was filtered off, and the productconcentrated under reduced pressure to obtain the target compound (614mg, 61%) as a light yellow oily substance.

(2) Manufacture of2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-4(3H)-quinazolinone

2-methyl-3-(4-hydroxyphenyl)-4-(3H)quinazolinone synthesized accordingto Example 1-(1) and -(2) (665 mg, 2.63 mmol),1,4-dioxaspiro[4.5]decan-8-ol (500 mg, 3.16 mmol) and triphenylphosphine (1.03 g, 3.96 mmol) were dissolvedin dry tetrahydrofuran (5mL), and cooled on an ice bath. Diisopropyl azodicarboxylate (777 uL,3.96 mmol) was dripped in at 0° C., and stirred at room temperature for48 hours. Distilled water was added, and the mixture extracted withethyl acetate. The organic phase was washed by saturated brine, theresidue was purified by silica gel column chromatography (hexane/ethylacetate=2/8-0/10), the ketal protector of the target compound wasobtained, and deprotection was then performed. 10% hydrochloric acidaqueous solution was added to the residue, and stirred at roomtemperature for 3 hours. 2N sodium hydroxide aqueous solution was added,and the mixture extracted with ethyl acetate. The organic phase waswashed by saturated brine solution and dried with anhydrous sodiumsulfate. The product was purified by silica gel column chromatography(chloroform/methanol=20/1) to obtain the target substance (511 mg, 49%)as a light orange solid.

(3) Manufacture ofcis-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinoneandtrans-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone

2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-4(3H)-quinazolinone (484 mg,1.39 mmol) and pyrrolidine (99 mg, 1.39 mmol) were dissolved in 0.5Mzinc(II) chloride/sodium cyanoborohydride methanol aqueous solution (1.7mL), and stirred at room temperature for 3 hours. 2N sodium hydroxideaqueous solution was added, and the mixture was extracted with ethylacetate. The organic phase was washed by saturated brine and dried withanhydrous sodium sulfate. The product was purified by silica gel columnchromatography (hexane/ethyl acetate=8/2-5/5), and the cis-isomer (260mg) and trans-isomer (180 mg) of the title compound were respectivelyobtained as colorless solids.cis-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone

¹HNMR (400 MHz,CDCl₃,δppm): 1.58-1.66 (2H,m), 1.73-1.81 (8H,m),2.10-2.13 (2H,m), 2.26 (3H,s), 2.61 (4H,brs), 4.53 (1H,m), 7.01(2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.1 Hz), 7.65(1H,d,J=8.1 Hz), 7.74 (1H,t,J=8.1 Hz), 8.24 (1H,d,J=8.1 Hz)trans-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone

¹HNMR (400 MHz,CDCl₃,δppm): 1.07-1.66 (4H,m), 1.77-1.81 (4H,m),2.16-2.06 (4H,m), 2.25 (3H,s), 2.61 (4H,brs), 4.19-4.26 (1H,m), 7.00(2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.1 Hz), 7.65(1H,d,J=8.1 Hz), 7.74 (1H,t,J=8.1 Hz), 8.25 (1H,d,J=8.1 Hz

Example 1183-{4-[(1-cyclopentyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone(racemic mixture) (1) Manufacture of 1-benzyl-3-pyrrolidinol

1-benzyl-3-pyrrolidinone was reduced with sodium borohydride accordingto Example 117-(1), and the target compound was obtained.

(2) Manufacture of3-{4-[(1-benzyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

1-benzyl-3-pyrrolidinol and 2-methyl-3-(4-hydroxyphenyl)-4-(3H)quinazolinone synthesized according to Example 1-(1) and -(2) wereetherated by the Mitsunobu reaction according to Example 117-(2), andthe target compound was thus obtained.

(3) Manufacture of3-{4-[(3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

The target compound was obtained by catalytic reduction of3-{4-[(1-benzyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinoneusing palladium hydroxide as catalyst in methanol.

(4) Manufacture of3-{4-[(1-cyclopentyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by reduction amination according toExample 88-(3), using3-{4-[(3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone andcyclopentanone.

¹HNMR (400 MHz,CDCl₃,δppm): 1.45-1.57 (2H,m), 1.70-1.73 (4H,m),1.72-1.85 (2H,m), 1.83-2.04 (1H,m), 2.25 (3H,s), 2.31-2.36 (1H,m),2.46-2.52 (1H,m),2.52-2.61 (1H,m), 2.79-2.84 (2H,m), 3.00-2.97 (1H,m),4.82-4.87 (1H,m), 6.96 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.44(1H,t,J=8.1 Hz), 7.64 (1H,d,J=8.1 Hz), 7.74 (1H,t,J=8.1 Hz), 8.24(1H,d,J=8.1 Hz)

Example 1193-{4-[(1-cyclobutyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone(racemic mixture)

The title compound was obtained by reductive amination according to themethod of Example 118, using3-{4-[(3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone andcyclobutanone.

¹HNMR (400 MHz,CDCl₃,δppm): 1.68-1.78 (2H,m), 1.94-2.07 (5H,m), 2.25(3H,s), 2.30-2.35 (1H,m), 2.46-2.52 (1H,m), 2.71-2.76 (2H,m), 2.86-2.91(1H,m), 2.93-3.00 (1H,m), 4.83-4.87 (1H,m), 6.96 (2H,d,J=8.8 Hz), 7.12(2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.1 Hz), 7.64 (1H,d,J=8.1 Hz), 7.74(1H,t,J=8.1 Hz), 8.24 (1H,d,J=8.1 Hz)

Example 120 3-{4-[(1-cyclopentyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone (Racemic Mixture) (1) Manufacture of3-{4-[(4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

2-methyl-3-(4-hydroxyphenyl)-4(3H)quinazolinone synthesized as inExample 1-(2) and 1-(t-butoxycarbonyl)-4-hydroxy azepan were etheratedby the Mitsunobu reaction according to the method of Example 117-(2),and the target compound was obtained by deprotection withtrifluoroacetic acid.

(2) Manufacture of3-{4-[(1-cyclopentyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by reductive amination according toExample 117-(3), using3-{4-[(4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone andcyclopentanone.

¹HNMR (400 MHz,CDCl₃,δppm): 1.47-1.59 (4H,m), 1.63-1.75 (2H,m),1.83-1.97 (4H,m), 2.02-2.16 (2H,m), 2.17-2.28 (5H,m), 2.73-2.87(2H,m),2.88-2.97 (2H,m), 2.98-3.07 (1H,m), 4.57-4.64 (1H,m), 6.97(2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.43 (1H,t,J=8.0 Hz), 7.64(1H,d,J=7.2 Hz), 7.73 (1H,t,J=7.2 Hz), 8.23 (1H,d,J=8.0 Hz)

Example 1213-{4-[(1-cyclobutyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by reductive amination according toExample 120, using3-{4-[(4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone andcyclobutanone.

¹HNMR (400 MHz,CDCl₃,δppm) 1.56-1.69 (4H,m), 1.80-1.89 (4H,m), 1.98-2.06(2H,m), 2.08-2.19 (2H,m), 2.24 (3H,s), 2.39-2.50 (2H,m), 2.53-2.62(2H,m), 2.85-2.95 (1H,m), 4.54-4.61 (1H,m), 6.96 (2H,d,J=8.8 Hz), 7.10(2H,d,J=8.8 Hz), 7.43 (1H,t,J=8.0 Hz), 7.63 (1H,d,J=7.2 Hz), 7.72(1H,t,J=7.2 Hz), 8.23 (1H,d,J=8.0 Hz)

Example 122 3-methyl-2-{4-[3-(1-piperidinyl)propoxy]phenyl}-1(2H)-isoquinolinone (1) Manufacture of3-(1-hydroxyethyl)-2-benzofuran-1(3H)-one

A dry tetrahydrofuran solution (100 mL) of lithium diisopropyl amide(26.9 mmol) was cooled to −78 degree in a current of nitrogen, and atetrahydrofuran solution (100 mL) of phthalide (3.0 g, 22.4 mmol) wasdripped in. After stirring at −78° C. for 30 minutes, acetaldehyde (1.19g, 26.9 mmol) was slowly added and stirred at −50° C. for 4 hours. Afterthe temperature had risen to room temperature, distilled water was addedand the mixture extracted with ethyl acetate. The organic phase waswashed with distilled water and saturated brine, and dried withanhydrous sodium sulfate. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/6), and the target compound (1.96g, 49%) was obtained as a yellow oily residue.

(2) Manufacture of 3-methyl-1H-isochroman-1-one

3-(1-hydroxyethyl)-2-benzofuran-1(3H)-one (1.3 g, 7.30 mmol) andp-toluenesulfonic acid monohydrate (3.46 g, 18.2 mmol) were dissolved intoluene (50 mL), and refluxed for 4 hours. Saturated sodium hydrogencarbonate aqueous solution was added, and the mixture extracted withethyl acetate. The organic phase was washed with saturated sodiumhydrogen carbonate aqueous solution and saturated brine, and dried withanhydrous sodium sulfate. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=10/0-5/5), and the target compound(0.64 g, 55%) was obtained as an orange solid.

(3) Manufacture of 2-(2-oxopropyl)benzoic acid

3-methyl-1H-isochroman-1-one (320 mg, 2.0 mmol) was dissolved in ethanol(5 mL), 2N sodium hydroxide aqueous solution (3 mL) was added, andstirred at 80° C. for 5 hours. Ethanol was distilled off under reducedpressure, 8N hydrochloric acid aqueous solution was added, and themixture extracted with ethyl acetate. The organic phase was dried withanhydrous sodium sulfate, concentrated and dried to obtain the targetcompound (280 mg, 79%) as a yellow solid.

(4) Manufacture of 2-(4-methoxyphenyl)-3-methyl-1(2H)-isoquinolinone

2-(2-oxopropyl)benzoic acid (100 mg, 0.56 mmol), 4-methoxyaniline (76mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.84 mmol) and pyridine (0.5 mL) were dissolved inchloroform (5 mL) and stirred at room temperature overnight. Chloroformwas added, the organic phase was washed by aqueous citric acid solution,sodium hydrogen carbonate aqueous solution and saturated brine in thatorder, and dried with anhydrous sodium sulfate. The product was purifiedby silica gel column chromatography (hexane/ethyl acetate=10/0-3/7) toobtain the target compound (66 mg, 44%) as a light brown solid.

(5) Manufacture of 2-(4-hydroxyphenyl)-3-methyl-1(2H)-isoquinolinone

2-(4-methoxyphenyl)-3-methyl-1(2H)-isoquinolinone (56 mg, 0.21 mmol) wasdissolved in dry methylene chloride, a 1M methylene chloride solution(0.63 mL) of boron tribromide was slowly added at −10° C., and stirredat room temperature for 2 hours. A saturated sodium hydrogen carbonateaqueous solution was added to the reaction mixture, and the methylenechloride distilled off under reduced pressure. 8N hydrochloric acidaqueous solution was added, and the solid precipitate was filtered offand dried to obtain the target compound (48 mg, 91%) as a colorlesssolid.

(6) Manufacture of3-methyl-2-{4-[3-(1-piperidinyl)propoxy]phenyl}-1(2H)-isoquinolinone

2-(4-hydroxyphenyl)-3-methyl-1(2H)-isoquinolinone (30 mg, 0.12 mmol),1-(3-bromopropyl)piperidine hydrobromide (51 mg, 0.18 mmol) andpotassium carbonate (49 mg, 0.36 mmol) were mixed in dimethylformamide(3 mL) and stirred at 80° C. for 3 hours. The solvent was distilled offunder reduced pressure, distilled water was added. and the mixtureextracted with ethyl acetate. The organic phase was dried with anhydroussodium sulfate, and the product purified by silica gel columnchromatography (chloroform/methanol=20/1) to obtain the title compound(18 mg, 40%) as a colorless solid.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.49 (2H,m), 1.56-1.63 (4H,m),1.97-2.04 (5H,m), 2.38-2.48 (4H,brs), 2.51 (2H,t,J=7.0 Hz), 4.06(2H,t,J=6.4 Hz), 6.42 (1H,s), 7.01 (2H,d,J=8.8 Hz), 7.13 (2H,d,J=8.8Hz), 7.39-7.47 (2H,m), 7.63 (1H,t,J=8.0 Hz), 8.37 (1H,d,J=8.0 Hz)

Example 1232-{4-[(1-cyclobutyl-4-piperidinyl)oxy-one]phenyl}-3-methyl-1(2H)-isoquinolinone

A Mitsunobu reaction and a reductive amination reaction were performedin that order according to the method of Example 88, using the2-(4-hydroxyphenyl)-3-methyl-1(2H)-isoquinolinone synthesized in Example122-(5), N-(t-butoxycarbonyl)-4-piperidinol and cyclobutanone asstarting materials, and the title compound was thus obtained as acolorless solid.

¹HNMR (400 MHz, CDCl₃,δppm): 1.62-1.77 (2H,m), 1.82-1.98 (4H,m), 2.02(3H,s), 2.02-2.10 (4H,m), 2.16-2.26 (2H,m), 2.60-2.69 (2H,m), 2.72-2.80(1H,m), 4.35-4.42 (1H,m), 6.42 (1H,s), 7.01 (2H,d,J=8.8 Hz), 7.13(2H,d,J=8.8 Hz), 7.40-7.44 (2H,m), 7.63 (1H,t,J=8.0 Hz), 8.37(1H,d,J=8.0 Hz)

Example 1242-methyl-3-[4-{[3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone(trans isomer) (1) Manufacture of(1)3-{4-[(3-hydroxycyclopentyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone

3-(4-hydroxyphenyl)-2-methyl-4(3H)-quinazolinone (300 mg, 1.19 mmol),1,3-cyclopentane diol (242 mg, 2.37 mmol) and triphenylphosphine (468mg, 1.78 mmol) were dissolved in tetrahydrofuran (3 mL), and diisopropylazodicarboxylate (0.35 mL, 1.78 mmol) was dripped in at 0° C. andstirred at room temperature for 2 hours. Distilled water was added toreaction mixture, and the mixture extracted with ethyl acetate. Theorganic phase was washed by saturated brine and dried by anhydrousmagnesium sulfate. The product was purified by silica gel columnchromatography (hexane/ethyl acetate=40/60-0/100), and the targetcompound (520 mg) was obtained as a light brown oily residue.

(2) Manufacture of3-[4-({3-[(methylsulfonyl)oxy]cyclopentyl}oxy)phenyl]-2-methyl-4(3H)-quinazolinone

3-{4-[(3-hydroxycyclopentyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone(520 mg, 1.19 mmol) and triethylamine (0.33 mL, 2.32 mmol) were mixed inmethylene chloride and cooled on an ice bath. Mesyl chloride (0.12 mL,1.55 mmol) was dripped in and stirred for 10 minutes at roomtemperature. Distilled water was added to the reaction mixture, and themixture extracted with ethyl acetate. The organic phase was washed withdistilled water, and dried by anhydrous magnesium sulfate. The residuewas concentrated to dryness, and the target compound (553 mg) was thusobtained.

(3) Manufacture of2-methyl-3-[4-{[3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazollnone(trans isomer)

3-[4-({3-[(methylsulfonyl)oxy]cyclopentyl}oxy)phenyl]-2-methyl-4(3H)-quinazolinone(550 mg, 1.33 mmol), pyrrolidine (474 mg, 6.7 mmol) and potassiumcarbonate (277 mg, 2.0 mmol) were mixed in dimethylformamide (10 mL) andstirred at 80° C. overnight. Distilled water was added, and the mixtureextracted with ethyl acetate. The organic phase was dried by anhydrousmagnesium sulfate, and the obtained residue was purified by silica gelcolumn chromatography (chloroform/methanol=20/1) to obtain the titlecompound (143 mg) as a colorless solid.

2-methyl-3-[4-{[(3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone(trans isomer)

¹HNMR (400 MHz,CDCl₃,δppm): 1.57-1.67 (1H,m), 1.78-1.81 (4H,m),1.85-1.92 (2H,m), 2.03-2.08 (1H,m), 2.14-2.19 (1H,m), 2.22-2.23 (1H,m),2.24 (3H,s), 2.76-2.83 (1H,m), 4.81-4.86 (1H,m), 6.96 (2H,d,J=8.8 Hz),7.11 (2H,d,J=8.8 Hz), 7.44 (1H,t,J=8.1 Hz), 7.66 (1H,d,J=8.1 Hz), 7.73(1H,t,J=8.1 Hz), 8.23 (1H,d,J=8.1 Hz)

Example 1253-{4-[3-(7-azabicyclo[2.2.1]hepto-7-yl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 7-azabicyclo[2.2.1]heptane hydrochloride asstarting materials. 7-azabicyclo[2.2.1]heptane hydrochloride wasmanufactured by the method described in the literature (J. Am. Chem.Soc., 2003, Vol. 125, p. 15191).

¹HNMR (400 MHz,CDCl₃,δppm): 1.34-1.35 (4H,m), 1.76-1.84 (4H, m),2.02-2.09 (2H,m), 2.28 (3H,s), 2.59-2.63 (2H,m), 3.37 (2H, brs), 4.12(2H,t,J=6.2 Hz), 7.04 (2H,d, J=9.0 Hz), 7.16 (2H,d,J=8.4 Hz), 7.46-7.50(1H,m), 7.67 (1H,d,J=7.8 Hz), 7.76-7.80 (1H,m), 8.28 (1H,dd,J=8.6, 1.6Hz)

Example 1263-{4-[3-(8-azabicyclo[3.2.1]octo-8-yl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone(1) Manufacture of 8-azabicyclo[3.2.1]octane hydrochloride

Tropane (11.0 mL, 7.44 mmol) was dissolved in toluene (10 mL),chloroethyl carbonate (2.2 mL, 23 mmol) was added slowly, and themixture stirred at 80° C. for 24 hours. Distilled water was added to thereaction mixture, and the mixture extracted with ethyl acetate. Theorganic phase was dried and concentrated by anhydrous magnesium sulfate.The obtained oily residue was dissolved in concentrated hydrochloricacid (10 mL), and heated with stirring at 100° C. for 2 hours. Thesolvent was distilled off under reduced pressure, toluene was added tothe residue, and the mixture distilled under reduced pressure to obtainthe target substance (820 mg, 72%) as a colorless solid.

(2) Manufacture of3-{4-[3-(8-azabicyclo[3.2.1]octo-8-yl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic-acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 8-azabicyclo[3.2.1]octane hydrochloride asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.37-2.06 (12H,m), 2.60 (2H,t,J=7.2 Hz),3.29 (2H,brs), 4.13 (2H,t,J=6.2 Hz), 7.07 (2H,d,J=6.1 Hz), 7.17(2H,d,J=6.1H-z), 7.46-7.50 (1H,m), 7.69 (1H,d,J=7.8 Hz), 7.76-7.80(1H,m), 8.29 (1H,dd,J=7.8, 1.2 Hz)

Example 1273-{4-[3-(3,3-difluoropyrrolidin-1-yl)propoxy]phenyl}-2-methyl-S-(trifluoromethyl)-4(3H)-quinazolinonetrifluoroacetate

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 3,3-difluoropyrrolidine hydrochloride asstarting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 2.27 (3H,s), 2.29 (2H,m), 2.70 (2H,m), 3.58(2H,dd,J=8.8, 8.8 Hz), 3.81 (2H,brs), 4.02 (2H,m), 4.23 (2H,t,J=5.6 Hz),7.17 (2H,d,J=8.8 Hz), 7.33 (2H,d,J=8.8 Hz), 7.95 (3H,m)

Example 1283-(4-{3-[(3R)-3-fluoropyrrolidin-1-yl]propoxy}phenyl)-2-methyl-5-(trifluoromethyl)-4(3H)-quinazolinonetrifluoroacetate

The title compound was obtained by the method according to Example 1,using 2-amino-6-(trifluoromethyl)benzoic acid, acetic anhydride,4-aminophenol, 1,3-bromochloropropane and (3R)-3-fluoropyrrolidinehydrochloride as starting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 2.20-2.80 (2H,m), 2.28 (3H,s), 2.31 (2H,m),3.20-3.60 (2H,m), 3.53 (2H,m), 3.80-4.20 (2H,m), 4.22 (2H,t,J=5.6 Hz),5.49 (1H,d,J=60 Hz), 7.17 (2H,d,J=9.2 Hz), 7.32 (2H,d,J=9.2 Hz), 7.95(3H,m)

Example 1293-{4-[3-(4,4-difluoropiperidin-1-yl)propoxy]phenyl}-2-methyl-5-(trifluoromethyl)-4(3H)-quinazolinonetrifluoroacetate

The title compound was obtained by the method according to Example 1,using 2-amino-6-(trifluoromethyl)benzoic acid, acetic anhydride,4-aminophenol, 1,3-bromochloropropane and 4,4-difluoropiperidinehydrochloride as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 2.20-2.60 (6H,m), 2.27 (3H,s), 3.20-3.50(2H,m), 3.49 (2H,t,J=8.0 Hz), 3.78 (2H,m), 4.23 (2H,t,J=5.6 Hz), 7.17(2H,d,J=6.6 Hz), 7.32 (2H,d,J=6.6 Hz), 7.95 (3H,m)

Example 1303-{4-[3-(4-fluoropiperidin-1-yl)propoxy]phenyl}-2-methyl-5-(trifluoromethyl)-4(3H)-quinazolinonetrifluoroacetate

The title compound was obtained by the method according to Example 1,using 2-amino-6-(trifluoromethyl) benzoic acid, acetic anhydride,4-aminophenol, 1,3-bromochloropropane and 4-fluoropiperidinehydrochloride as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 2.18-2.43 (9H,m), 3.11 (2H,m), 3.29(2H,t,J=7.8 Hz), 3.60 (2H,m), 4.13 (2H,t,J=5.6 Hz), 5.02 (1H,m), 7.03(2H,d,J=9.0 Hz), 7.19 (2H,d,J=9.0 Hz), 7.82-7.83 (1H,m), 7.89-7.90(2H,m)

Example 1313-{4-[3-(3,3-difluoropiperidin-1-yl)propoxy]phenyl}-2-methyl-5-(trifluoromethyl)-4(3H)-quinazolinonetrifluoroacetate

The title compound was obtained by the method according to Example 1,using 2-amino-6-(trifluoromethyl)benzoic acid, acetic anhydride,4-aminophenol, 1,3-bromochloropropane and 3,3-difluoropiperidinehydrochloride as starting materials.

¹HNMR (400 MHz,DMSO-d6,δppm): 2.15-2.18 (5H,m), 3.32-3.34 (2H,m),3.74-3.76 (8H,m), 4.14 (2H,t,J=5.9 Hz), 7.11 (2H,d,J=9.0 Hz), 7.39(2H,d,J=9.0 Hz), 7.92-7.99 (3H,m)

Example 1323-{4-[3-(3-fluoropiperidin-1-yl)propoxy]phenyl}-2-methyl-S-(trifluoromethyl)-4(3H)-quinazolinonetrifluoroacetate (Racemic Mixture)

The title compound was obtained by the method according to Example 1,using 2-amino-6-(trifluoromethyl)benzoic acid, acetic anhydride,4-aminophenol, 1,3-bromochloropropane and 3-fluoropiperidinehydrochloride as starting materials.

¹HNMR (400 MHz,DMSO-d6,δppm): 1.66-2.01 (4H,m), 2.15-2.17 (5H,m),3.15-3.38 (4H,m), 3.83-4.09 (4H,m), 5.17 (1H,m), 7.11 (2H,d,J=9.0 Hz),7.39 (2H,d,J=9.0 Hz), 7.94-7.98 (3H,m)

Example 1332-methyl-3-(4-{3-[(3R)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and (3R)-3-methylpiperidine (R)-(−)-mandelate asstarting materials. (3R)-3-methylpiperidine (R)-(−)-mandelate wasmanufactured by the method described in the literature (J. Org. Chem.,1987, Vol. 52, p. 5466).

¹HNMR (400 MHZ,CDCl₃,δppm): 0.87 (4H,m), 1.50-1.95 (6H,m), 2.00 (2H,m),2.26 (3H,s), 2.50 (2H,t,J=6.8 Hz), 2.87 (2H,m), 4.07 (2H,t,J=6.4 Hz),7.05 (2H,d,J=8.6 Hz), 7.15 (2H,d,J=8.6 Hz), 7.46 (1H,t,J=8.0 Hz), 7.67(1H,d,J=8.0 Hz), 7.76 (1H,t,J=8.4 Hz), 8.27 (1H,d,J=8.0 Hz)

Example 1343-(4-{3-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]propoxy}phenyl)-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and (2R,5R)-2,5-dimethylpyrrolidine as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.00 (6H,d,J=6.0 Hz), 1.40 (2H,m), 2.05(4H,m), 2.26 (3H,s), 2.60 (1H,m), 2.80 (1H,m), 3.10 (2H,m), 4.10 (2H,m),7.05 (2H,d,J=8.8 Hz), 7.15 (2H,d,J=8.8 Hz), 7.46 (1H,t,J=8.0 Hz), 7.67(1H,d,J=8.0 Hz), 7.76 (1H,t,J=7.6 Hz), 8.27 (1H,d,J=8.0 Hz)

Example 1352-methyl-3-(4-{3-[3-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by the method according to Example 1,using anthranilic acid, acetic anhydride, 4-aminophenol,1,3-bromochloropropane and 3-methylpyrrolidine as starting materials.3-methylpyrrolidine was manufactured by the method described in theliterature (J. Med. Chem., 2000, Vol. 43, p. 4388).

¹HNMR (400 MHz,CDCl₃,δppm) 1.05 (3H,d,J=6.8 Hz), 1.38-1.42 (1H,m),2.02-2.09 (4H,m), 2.26 (3H,s), 2.28-2.30 (1H,m), 2.54-2.56 (1H,m),2.63-2.72 (2H,m), 2.78-2.80 (1H,m), 2.92 (1H,t,J=8.3 Hz), 4.09(2H,t,J=6.3 Hz), 7.04 (2H,td,J=6.0, 3.6 Hz), 7.15 (2H,td,J=6.0, 3.6 Hz),7.46 (1H,t,J=8.0 Hz), 7.67 (1H,d,J=7.8 Hz), 7.74-7.78 (1H,m), 8.27(1H,dd,J=7.8, 1.5 Hz)

Example 1365-methoxy-3-[4-(3-piperidin-1-yl-propoxy)phenyl]-2-propyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-methoxybenzoic acid, butyric anhydride and4-(3-piperidin-1-yl propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.87 (3H,t,J=7.6 Hz), 1.41-1.50 (2H,m),1.52-1.63 (4H,m), 1.66-1.73 (2H,m), 1.97-2.04 (2H,m), 2.36-2.46 (6H,m),2.51 (2H,t,J=7.6 Hz), 3.94 (3H,s), 4.06 (2H,t,J=6.4 Hz), 6.86(1H,d,J=7.6 Hz), 7.01 (2H,d,J=9.2 Hz), 7.09 (2H,d,J=9.2 Hz), 7.25(1H,d,J=8.4 Hz), 7.64 (1H,t,J=8.4 Hz)

Example 1375-methoxy-2-propyl-3-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-methoxybenzoic acid, butyric anhydride and4-(3-pyrrolidin-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 0.87 (3H,t,J=7.6 Hz), 1.64-1.84 (2H,m),1.78-1.82 (4H,m), 2.02-2.08 (2H,m), 2.37 (2H,t, J=8.0 Hz), 2.52-2.56(4H,m), 2.65 (2H,t,J=7.6 Hz), 3.94 (3H,s), 4.08 (2H,t,J=6.4 Hz), 6.86(1H,dd,J=0.8, 8.4 Hz), 7.02 (2H,d,J=9.2 Hz), 7.10 (2H,d,J=9.2 Hz), 7.25(1H,dd,J=0.8, 8.4 Hz), 7.64 (1H,t,J=8.4 Hz)

Example 1382-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone(1) Manufacture of 3-[(2S)-2-methylpyrrolidin-1-yl]propan-1-ol

(2S)-2-methylpyrrolidine hydrobromide (2.70 g, 16.3 mmol),3-bromopropanol (2.49 g, 17.9 mmol) and potassium carbonate (6.75 g,48.9 mmol) were mixed in tetrahydrofuran (20 mL), and stirred at 60° C.for 18 hours. The precipitate was filtered off, and the filtrate wasconcentrated. The residue was distilled under reduced pressure, and thetarget compound (1.88 g, 80%) was thus obtained as a colorless oilysubstance. (2S)-2-methyl-pyrrolidine hydrobromide was manufactured bythe method described in the literature (J. Org. Chem., 1989, Vol. 54, p.209) using D-prolinol as starting material.

(2) Manufacture of (2S)-2-methyl-1-[3-(4-nitrophenoxy)propyl]pyrrolidine

The target compound was obtained by the method according to Example 18,using 3-[(2S)-2-methylpyrrolidin-1-yl]propanol and 4-nitrophenol asstarting materials.

(3) Manufacture of 4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}aniline

The target compound was obtained by catalytic reduction of(2S)-2-methyl-1-[3-(4-nitrophenoxy)propyl]pyrrolidine in methanol, usinga palladium charcoal catalyst.

(4) Manufacture of2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, acetic anhydride and4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}aniline as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.12 (3H,d,J=6.0 Hz), 1.40-1.50 (1H,m),1.60-2.37 (11H,m), 2.97-3.03 (1H,m), 3.18-3.23 (1H,m), 4.07-4.11 (2H,m),7.05 (2H,d,J=9.2 Hz), 7.15 (2H,d,J=9.2 Hz), 7.46 (1H,t,J=7.6 Hz), 7.67(1H,d,J=7.6 Hz), 7.76 (1H,t,J=7.6 Hz), 8.27 (1H,d,J=7.6 Hz)

NMR data for 4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}aniline used formanufacturing the compound of this example is shown below.

¹HNMR (400 MHz,CDCl₃,δppm): 1.60 (3H,d, J=6.4 Hz), 1.93-2.12 (2H,m),2.18-2.30 (3H,m), 2.41-2.49 (1H,m), 2.95-3.34 (5H,m), 3.46-3.53 (1H,m),3.86-3.92 (1H,m), 4.07 (2H,t,J=6.4 Hz), 6.89 (2H,d, J=9.2 Hz), 7.31(2H,d,J=9.2 Hz)

Example 1392,5-dimethyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-methyl benzoic acid, acetic anhydride and4-{3-[(2S)-2-methyl-pyrrolidin-1-yl]propoxy}aniline as startingmaterials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.11 (3H,d,J=6.0 Hz), 1;38-1.48 (1H,m),1.59-2.33 (11H,m), 2.82 (3H,s), 2.97-3.03 (1H,m), 3.17-3.22 (1H,m),4.06-4.10 (2H,m), 7.04 (2H,d,J=9.2 Hz), 7.15 (2H,d,J=9.2 Hz), 7.21(1H,d,J=7.2 Hz), 7.50 (1H,d,J=7.2 Hz), 7.59 (1H,t,J=7.2 Hz)

Example 1402,6-dimethyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-5-methyl benzoic acid, acetic anhydride and4-{3-[(2S)-2-methyl-pyrrolidin-1-yl]propoxy}aniline as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.12 (3H,d,J=6.0 Hz), 1.38-1.48 (1H,m),1.59-2.37 (11H,m), 2.48 (3H,s), 2.97-3.03 (1H,m), 3.17-3.23 (1H,m),4.07-4.11 (2H,m), 7.04 (2H,d,J=9.2 Hz), 7.14 (2H,d,J=9.2 Hz), 7.57-7.58(2H,m), 8.05 (1H,s)

Example 1412-ethyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, propionic anhydride and4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}aniline as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.12 (3H,d,J=6.0 Hz), 1.22 (3H,t,J=7.2 Hz),1.40-1.50 (1H,m), 1.60-2.37 (8H,m), 2.47 (2H,q, J=7.2 HZ), 2.97-3.04(1H,m), 3.18-3.23 (1H,m), 4.07-4.11 (2H,m), 7.05 (2H,d,J=9.2 Hz), 7.15(2H,d,J=9.2 Hz), 7.45 (1H,t,J=7.6 Hz), 7.71 (1H,d,J=7.6 Hz), 7.76(1H,t,J=7.6 Hz), 8.27 (1H,d,J=7.6 Hz)

Example 1426-chloro-2-ethyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-chloroisonicotinic acid, propionic anhydride and4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}aniline as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.11 (3H,d,J=6.0 Hz), 1.23 (3H,t,J=7.2 Hz),1.40-1.50 (1H, m), 1.60-2.37 (8H,m), 2.46 (2H,q,J=7.2 Hz), 2.97-3.04(1H,m), 3.18-3.23 (1H,m), 4.08-4.11 (2H,m), 7.06 (2H,d,J=9.2 Hz), 7.12(2H,d,J=9.2 Hz), 8.06 (1H,d,J=0.8 Hz), 8.94 (1H,d,J=0.8 Hz)

Example 1436-methoxy-2-methyl-3-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using a 2-amino-5-methoxybenzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.79-1.83 (4H,m), 2.03-2.09 (2H,m), 2.23(3H,s), 2.52-2.58 (4H,m), 2.66 (2H,t,J=7.2 Hz), 3.91 (3H,s), 4.10(2H,t,J=6.4 Hz), 7.05 (2H,d,J=9.2 Hz), 7.14 (2H,d,J=9.2 Hz), 7.36(1H,dd,J=2.8, 8.8 Hz), 7.61 (1H,d,J=8.8 Hz), 7.63 (1H, d, J=3.2 Hz)

Example 1446-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:102-106° C.)by the method according to Example 18, using 2-amino-5-methoxybenzoicacid, acetic anhydride and4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}aniline as startingmaterials, followed by recrystallization (ethyl acetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.12 (3H,d,J=6.0 Hz), 1.38-1.48 (1H,m),1.59-2.37 (11H,m), 2.97-3.03 (1H,m), 3.17-3.23 (1H,m), 3.91 (3H,s),4.08-4.11 (2H,m), 7.05 (2H,d,J=9.2 Hz), 7.15 (2H,d,J=9.2 Hz), 7.35(1H,dd,J=2.8, 8.8 Hz), 7.61 (1H,d,J=9.2 Hz), 7.63 (1H,d,J=3.2 Hz)

Example 1452-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone(1) Manufacture of 3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol

(3S)-3-methyl-piperidine/(S)-(+)-mandelate (19.9 g, 79.1 mmol),3-bromo-1-propanol (10 g, 71.9 mmol) and potassium carbonate (14.9 g,108 mmol) were mixed in tetrahydrofuran (200 mL), and heated underreflux for 30 hours. The insoluble matter was filtered off, the filtratewas concentrated, and ethyl acetate and hexane were added to theresidue. The insoluble matter produced was filtered off, the filtratewas concentrated and the target substance (9.6 g, 85%) was obtained as acolorless oily material by distillation under reduced pressure.(3S)-3-methyl-piperidine (S)-(+)-mandelate was manufactured by themethod described in the literature (J. Org. Chem., 1987, Vol. 52, p.5466).

(2) Manufacture of 4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}anilinemonotosylate

4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline was obtained as alight brown oily substance by the method according to Example 18, using4-nitrophenol and 3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol as startingmaterials. The obtained oily substance was dissolved in ethyl acetate, 1Eq of a methanol solution of p-toluenesulfonic acid monohydrate wasadded, and the target compound was obtained as a light peach-coloredsolid by filtering off the solid produced.

(3) Manufacture of2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using anthranilic acid, acetic anhydride and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.87-0.89 (4H,m), 1.56-1.76 (5H,m),1.84-1.91 (1H,m), 2.02-2.06 (2H,m), 2.26 (3H,s), 2.53 (2H,t,J=7.2 Hz),2.85-2.93 (2H,m), 4.07 (2H,t,J=6.3 Hz), 7.04 (2H,d,J=9.0 Hz), 7.15(2H,d,J=9.0 Hz), 7.46 (1H,t,J=7.6 Hz), 7.67 (1H,d,J=7.6 Hz), 7.76(1H,t,J=7.6 Hz), 8.27 (1H,d,J=7.6 Hz)

NMR data for 4-{3-[(3S)-3-methyl piperidin-1-yl]propoxy}anilinemonotosylate used for manufacturing the compound of this example isshown below.

¹HNMR (400 MHz,CDCl₃/CD₃OD=10/1,5 ppm): 0.95-1.10 (4H,m), 1.87-1.92(2H,m), 2.02-2.32 (7H,m), 2.36 (3H,s), 2.51-2.58 (1H,m), 3.22-3.26(2H,m), 3.52-3.56 (1H,m), 3.66-3.69 (1H,m), 3.95 (2H,t,J=5.6 Hz),6.64-6.70 (4H,m), 7.19 (2H,d,J=8.3 Hz), 7.76 (2H,d,J=8.3 Hz)

Example 1465-bromo-2-methyl-3-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]-4(3H)-quinazolinone(1) Manufacture of 2-amino-6-bromobenzoic acid

The target compound was obtained by reducing 2-bromo-6-nitrobenzoic acidwith iron in a mixed solvent of methanol and ammonium chloride aqueoussolution. 2-bromo-6-nitrobenzoic acid was manufactured by the methoddescribed in the literature (J. Chem. Soc. Perkin Trans. 1, 1991, p.1565) using 2-bromo-6-nitrotoluene as starting material.

(2) Manufacture of5-bromo-2-methyl-3-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-bromobenzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.80-1.84 (4H,m), 2.03-2.09 (2H,m), 2.23(3H,s), 2.60-2.56 (4H,m), 2.68 (2H,t,J=7.6 Hz), 4.08 (2H,t,J=6.3 Hz),7.04 (2H,d,J=9.3 Hz), 7.14 (2H,d,J=8.8 Hz), 7.51 (1H,t,J=8.0 Hz), 7.62(1H,dd,J=8.3, 1.5 Hz), 7.70 (1H,dd, J=7.8, 1.5 Hz)

Example 1475-fluoro-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-fluorobenzoic acid, acetic anhydride and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.83-0.91 (4H,m), 1.54-1.73 (5H,m),1.83-1.89 (1H,m), 1.98-2.05 (2H,m), 2.24 (3H,s), 2.50 (2H,t,J=7.3 Hz),2.83-2.90 (2H,m), 4.07 (2H,t,J=6.3 Hz), 7.04 (2H,d,J=9.3 Hz), 7.07-7.12(1H,m), 7.13 (2H,d,J=9.3 Hz), 7.46 (1H,d,J=8.3 Hz), 7.70-7.65 (1H,m)

Example 1482-ethyl-5-fluoro-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-fluorobenzoic acid, propionic anhydride and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.85-0.90 (4H,m), 1.21 (3H,t,J=7.3 Hz)1.54-1.73 (5H,m), 1.83-1.90 (1H,m), 1.99-2.05 (2H,m), 2.44 (2H,q,J=7.5Hz), 2.50 (2H,t,J=7.3 Hz), 2.83-2.91 (2H,m), 4.07 (2H,t,J=6.3 Hz),7.02-7.14 (5H,m), 7.50 (1H,d,J=8.3 Hz), 7.70-7.64 (1H,m)

Example 1496-fluoro-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-fluoroisonicotinic acid, acetic anhydride and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate asstarting materials. 5-amino-2-fluoroisonicotinic acid was manufacturedby the method described in the literature (J. Chem. Soc. Perkin Trans.1, 1996, p. 2221).

¹HNMR (400 MHz, CDCl₃,δppm): 0.83-0.93 (4H,m), 1.61-1.75 (5H,m),1.86-1.92 (1H,m), 2.01-2.08 (2H,m), 2.28 (3H,s), 2.53 (2H,t,J=7.3 Hz),2.94-2.85 (2H,m), 4.08 (2H,t,J=6.3 Hz), 7.06 (2H,d,J=9.3 Hz), 7.14(2H,d,J=9.3 Hz), 7.65 (1H,d,J=3.9 Hz), 8.77 (1H,s)

Example 1502-ethyl6-fluoro3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-fluoroisonicotinic acid, propionic anhydride and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.83-0.92 (4H,m), 1.23 (3H,t,J=7.3 Hz),1.56-1.74 (5H,m), 1.84-1.90 (1H,m), 2.00-2.07 (2H,m), 2.44-2.53 (4H,m),2.83-2.91 (2H,m), 4.08 (2H,t,J=6.3 Hz), 7.06 (2H,d,J=9.3 Hz), 7.13(2H,d,J=8.8 Hz), 7.65 (1H,d,J=3.9 Hz), 8.80 (1H,s)

Example 1516-chloro-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]-pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-chloroisonicotinic acid, acetic anhydride and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.83-0.92 (4H,m), 1.23 (3H,t,J=7.3 Hz),1.58-1.74 (5H,m), 1.84-1.90 (1H,m), 2.00-2.07 (2H,m), 2.44-2.53 (4H,m),2.91-2.84 (2H,m), 4.08 (2H,t,J=6.3 Hz), 7.06 (2H,d,J=9.3 Hz), 7.13(2H,d,J=9.3 Hz), 7.65 (1H,d,J=3.9 Hz), 8.80 (1H,s)

Example 1526-chloro-2-ethyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 18,using 5-amino-2-chloroisonicotinic acid, propionic anhydride and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.83-0.93 (4H,m), 1.23 (3H,t,J=7.3 Hz)1.58-1.74 (5H,m), 1.86-1.92 (1H,m), 2.01-2.07 (2H,m), 2.47 (2H,q,J=7.3Hz), 2.52 (2H,t, J=7.6 Hz), 2.92-2.85 (2H,m), 4.08 (2H,t,J=6.3 Hz), 7.06(2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 8.06 (1H,d,J=1.0 Hz), 8.94 (1H,d, J=1.0 Hz)

Example 1532-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-onemonohydrochloride

The title compound was synthesized as a white solid (m.p.:255-262° C.)by the method according to Example 18, using 2-aminonicotinic acid,acetic anhydride and 4-{3-[(3S)-3-methylpyridin-1-yl]propoxy}anilinemonotosylate as starting materials and treating with 1 Eq of a base (4Nethyl acetate solution), followed by recrystallization (ethanol/ethylacetate).

1H-NMR (400 MHz,CDCl₃/CD₃OD=10/1,δppm) 1.01 (3H,d,J=6.3 Hz), 1.05-1.15(1H,m), 1.90-1.99 (2H,m), 2.25-2.51 (8H,m), 2.57-2.64 (1H,m), 3.21-3.25(2H,m), 3.51-3.54 (1H,m), 3.63-3.67 (1H,m), 4.18 (2H,t, J=5.6 Hz), 7.06(2H,d, J=8.8 Hz), 7.19 (2H,d,J=8.8 Hz), 7.51 (1H,dd,J=7.8, 4.9 Hz), 8.66(1H,dd,J=7.8, 2.0 Hz), 9.03 (1H,dd,J=4.9, 2.0 Hz)

Example 1542-ethyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-onemonohydrochloride

The title compound was synthesized as a white solid (m.p.:245-252° C.)by the method according to Example 18, using 2-aminonicotinic acid,propionic anhydride and 4-{3-[(3S)-3-methylpyridin-1-yl]propoxy}anilinemonotosylate as starting materials and treating with 1 Eq of a base (4Nethyl acetate solution), followed by recrystallization (ethanol/ethylacetate).

¹HNMR (400 MHz,CDCl₃/CD₃OD=10/1,δppm): 0.99 (3H,d,J=6.3 Hz), 1.07-1.14(1H, m), 1.31 (3H,t,J=7.3 Hz), 1.88-1.99 (2H,m), 2.22-2.30 (1H,m),2.38-2.58 (7H,m), 3.16-3.22 (2H,m), 3.47-3.52 (1H,m), 3.60-3.64 (1H,m),4.17 (2H,t,J=5.4 Hz), 7.04 (2H,d,J=8.8 Hz), 7.17 (2H,d,J=8.8 Hz), 7.43(1H,dd,J=7.8, 4.1 Hz), 8.60 (1H,dd,J=7.8, 2.0 Hz), 9.00 (1H,dd,J=4.1,2.0 Hz)

Example 1552-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-onemonotosylate

The title compound was synthesized as a light yellow solid(m.p.:185-188° C.) by the method according to Example 18, using4-aminonicotinic acid, acetic anhydride and4-{3-[(3S)-3-methylpyridin-1-yl]propoxy}aniline monotosylate as startingmaterials and treating with 1 Eq of p-toluene sulfonic acid, followed byrecrystallization (ethanol/ethyl acetate).

¹HNMR (400 MHz,CDCl₃/CD₃OD=10/1,δppm): 0.99 (3H,d,J=6.8 Hz), 1.04-1.12(1H,m), 1.90-1.94 (2H,m), 2.06-2.21 (2H,m), 2.28-2.44 (10H,m), 3.27-3.32(2H,m), 3.56-3.60 (1H,m), 3.70-3.74 (1H,m), 4.15 (2H,t,J=5.6 Hz),7.04-7.07 (2H,m), 7.15-7.18 (2H,m), 7.21 (2H,d,J=7.8 Hz), 7.59(1H,d,J=5.9 Hz), 7.77 (2H,d,J=8.3 Hz), 8.85 (1H,d,J=5.9 Hz), 9.45 (1H,s)

Example 1562-ethyl-5-methoxy-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinonehydrochloride

The title compound was obtained by the method according to Example 18,using 2-amino-6-methoxybenzoic acid, propionic anhydride and4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.99 (3H,d,J=6.8 Hz), 1.04-1.15 (1H,m), 1.33(3H,t,J=7.3 Hz), 1.88-1.98 (2H,m), 2.22-2.31 (1H,m), 2.34-2.43 (1H,m),2.47-2.61 (4H,m), 2.98-3.05 (2H,m), 3.16-3.22 (2H,m), 3.50 (1H,d,J=10.2Hz), 3.63 (1H,d,J=11.2 Hz), 3.99 (3H,s), 4.19 (2H,t,J=5.1 Hz), 7.04-7.07(3H,m), 7.18 (2H,d,J=8.3 Hz), 7.82 (1H,t,J=8.3 Hz), 7.98 (1H,d,J=8.3 Hz)

Example 1572-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-2-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 151 using a palladium charcoal catalyst in thepresence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 0.85-0.93 (4H,m), 1.58-1.75 (5H,m),1.86-1.93 (1H,m), 2.01-2.08 (2H,m), 2.30 (3H,s), 2.53 (2H,t,J=7.6 Hz),2.93-2.86 (2H,m), 4.08 (2H,t,J=6.3 Hz), 7.06 (2H,d,J=8.8 Hz), 7.14(2H,d,J=8.8 Hz), 8.03 (1H,d,J=5.9 Hz), 8.68 (1H,d,J=5.4 Hz), 9.12 (1H,s)

Example 1582-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 152 using a palladium charcoal catalyst in thepresence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 0.83-0.92 (4H,m), 1.24 (3H,t,J=7.3 Hz)1.56-1.76 (5H,m), 1.85-1.92 (1H,m), 2.01-2.07 (2H,m), 2.46-2.54 (4H,m),2.85-2.92 (2H,m), 4.08 (2H,t,J=6.3 Hz), 7.06 (2H,d,J=9.3 Hz), 7.13(2H,d,J=8.8 Hz), 8.03 (1H,d,J=4.9 Hz), 8.67 (1H,d,J=4.9 Hz), 9.16 (1H,s)

Example 1598-fluoro-2-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinonehydrochloride

The title compound was obtained by the method according to Example 18,using 2-amino-3-fluorobenzoic acid, acetic anhydride and4-{(3-[(3S)-3-methyl-piperidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃/CD₃OD=10/1,δppm): 0.99 (3H,d,J=6.8 Hz), 1.05-1.14(1H,m), 1.88-1.98 (2H,m), 2.17-2.31 (3H,m), 2.39 (3H,s), 2.45-2.61(3H,m), 3.17-3.22 (2H,m), 3.50 (1H,d, J=11.7 Hz), 3.63 (1H,d,J=10.7 Hz),4.17 (2H,t,J=5.4 Hz), 7.04 (2H,d,J=8.3 Hz), 7.19 (2H,d,J=8.3 Hz),7.41-7.46 (1H,m), 7.50-7.55 (1H,m), 8.05 (1H,d,J=7.8 Hz)

Example 1608-fluoro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinonehydrochloride

The title compound was obtained by the method according to Example 18,using 2-amino 3-fluorobenzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃/CD₃OD=10/1,δppm) 2.09-2.18 (2H,m), 2.21-2.29(2H,m), 2.39-2.47 (5H,m), 2.86-2.95 (2H,m), 3.37-3.32 (2H,m), 3.83-3.89(2H,m), 4.18 (2H,t,J=5.4 Hz), 7.07 (2H,d,J=8.3 Hz), 7.22 (2H,d,J=8.8Hz), 7.46-7.52 (1H,m), 7.57 (1H,t,J=9.0 Hz), 8.06 (1H,d,J=8.3 Hz)

Example 1616-(2-fluoroethoxy)-2-methyl-3-[4-(3-piperidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by demethylation and alkylation of6-methoxy-2-methyl-3-[4-(3-piperidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone synthesized in Example 36 and2-fluoroethyl tosylate as starting materials by the method according toExample 192.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.48 (2H,m), 1.58-1.63 (4H,m),2.00-2.05 (2H,m), 2.23 (3H,s), 2.39-2.45 (4H,m), 2.51 (2H,t,J=7.2 Hz),4.07 (2H,t,J=6.4 Hz) 4.27-4.29 (1H,m), 4.34-4.36 (1H,m), 4.73-4.75(1H,m), 4.844.87 (1H,m), 7.04 (2H,d,J=9.2 Hz), 7.15 (2H,d,J=9.2 Hz),7.41 (1H,dd,J=2.8, 8.8 Hz), 7.61-7.64 (2H,m)

Example 1626-(2-fluoroethoxy)-2-methyl-3-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by demethylation and alkylation of6-methoxy-2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinonesynthesized in Example 143 by the method according to Example 192.

¹HNMR (400 MHz,CDCl₃,δppm): 1.81-1.84 (4H,m), 2.03-2.12 (2H,m), 2.23(3H,s), 2.57-2.63 (4H,m), 2.70 (2H,t,J=7.2 Hz), 4.10 (2H,t,J=6.4 Hz),4.27-4.29 (1H,m), 4.34-4.36 (1H,m), 4.73-4.75 (1H,m), 4.85-4.87 (1H,m),7.04 (2H,d,J=9.2 Hz), 7.14 (2H,d,J=9.2 Hz), 7.41 (1H,dd,J=2.8, 8.8 Hz),7.61-7.64 (2H,m)

Example 163 5-methoxy-2-methyl-3-[4-(3-pyrrolidin-1-yl propoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 18,using 2-amino-6-methoxybenzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.80-1.85 (4H,m), 2.03-2.10 (2H,m), 2.21(3H,s), 2.55-2.61 (4H,m), 2.66-2.70 (2H,m), 3.95 (3H,s), 4.08(2H,t,J=6.1 Hz), 6.87 (1H,d,J=8.3 Hz), 7.01 (2H,d,J=8.8 Hz), 7.11(2H,d,J=9.3 Hz), 7.23 (1H,d,J=8.3 Hz), 7.65 (1H, t, J=8.3 Hz)

Example 1645-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:144-146° C.)by the method according to Example 18, using 2-amino-6-methoxybenzoicacid, acetic anhydride and4-{3-[(3S)-3-methylpyridin-1-yl]propoxy}aniline monotosylate as startingmaterials, followed by recrystallization (ethyl acetate/diethylether/n-heptane).

¹HNMR (400 MHz,CDCl₃,δppm): 0.85-0.90 (4H,m), 1.58-1.74 (5H,m),1.83-1.91 (1H,m), 1.98-2.06 (2H,m), 2.21 (3H,s), 2.49-2.54 (2H,m),2.84-2.92 (3H,m), 3.95 (3H,s), 4.06 (2H,t,J=7.0 Hz), 6.87 (1H,d, J=8.3Hz), 7.01 (2H,d,J=8.8 Hz), 7.11 (2H,d,J=8.8 Hz), 7.23 (1H,d,J=8.3 Hz),7.65 (1H,t,J=8.3 Hz)

Example 1656-methoxy-2-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone(1) Manufacture of 6-methoxy-2-methyl-4H-3,1-benzoxazin-4-one

The target compound was obtained by the method according to Example1-(1), using 2-amino-5-methoxybenzoic acid and acetic anhydride asstarting materials.

(2) Manufacture of 6-methoxy-2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone

6-methoxy-2-methyl-4H-3,1-benzoxazon-4-one (80 mg, 0.42 mmol) and4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline monotosylate (176 mg,0.42 mmol) were dissolved in acetic acid (2 mL), and stirred at roomtemperature for 20 hours. Acetic acid was distilled off under reducedpressure, ethyl acetate and 1N sodium hydroxide aqueous solution wereadded, the mixture extracted with ethyl acetate and dried with anhydroussodium sulfate. After purifying by silica gel column chromatography(chloroform/methanol=20/1), the title compound (110 mg, 62%) wasobtained as colorless crystals by recrystallization (ethylacetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 0.84-0.91 (4H,m), 1.57-1.75 (5H,m),1.85-1.93 (1H,m), 2.01-2.08 (2H,m), 2.23 (3H,s), 2.51-2.56 (2H,m),2.85-2.94 (2H,m), 3.91 (3H,s), 4.08 (2H,t,J=6.3 Hz), 7.04 (2H,d,J=8.8Hz), 7.15 (2H,d,J=9.3 Hz), 7.36 (1H,dd,J=9.0, 3.2 Hz), 7.61 (1H,d,J=8.8Hz), 7.63 (1H,d,J=2.9 Hz)

Example 1666-(difluoromethoxy)-2-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 253,using3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinonesynthesized in Example 165 and sodium chlorodifluoroacetate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.84-0.92 (4H,m), 1.54-1.74 (5H,m),1.84-1.90 (1H,m), 1.99-2.06 (2H,m), 2.25 (3H,s), 2.51 (2H,t,J=7.3 Hz),2.92-2.84 (2H,m), 4.07 (2H,t,J=6.3 Hz), 6.61 (1H,t,J=73.4 Hz), 7.05(2H,d,J=8.8 Hz), 7.14 (2H,d,J=8.8 Hz), 7.53 (1H,dd,J=8.8, 2.9 Hz), 7.69(1H,d,J=8.8 Hz), 7.94 (1H,d, J=4 Hz)

Example 1675-(difluoromethoxy)-2-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 253,using5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinonesynthesized in Example 164 and sodium chlorodifluoroacetate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm) 0.83-0.92 (4H,m), 1.54-1.73 (5H,m), 1.83-1.90(1H,m), 1.99-2.06 (2H,m), 2.25 (3H,s), 2.50 (2H,t,J=7.6 Hz), 2.84-2.91(2H,m), 4.06 (2H,t,J=6.3 Hz), 6.67 (1H,t,J=75.9 Hz), 7.04 (2H,d,J=8.8Hz), 7.13 (2H,d,J=9.3 Hz), 7.24 (1H,d,J=7.3 Hz), 7.58 (1H,dd,J=8.3, 1.0Hz), 7.71 (1H,t,J=8.3 Hz)

Example 1687-methoxy-2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-4-methoxybenzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl-propoxy)aniline as starting materials.2-amino-4-methoxybenzoic acid was manufactured by the method describedin the literature (J. Chem. Soc. Perkin Trans. 1, 1997, p. 3261).

¹HNMR (400 MHz,CDCl₃,δppm): 1.79-1.82 (4H,m), 2.01-2.08 (2H,m), 2.24(3H,s), 2.53-2.56 (4H,m), 2.65 (2H,t,J=7.6 Hz), 3.93 (3H,s), 4.09(2H,t,J=6.3 Hz), 7.06-7.01 (4H,m), 7.14 (2H,d,J=8.8 Hz), 8.16(1H,d,J=8.8 Hz)

Example 1697-methoxy-2-methyl-3-[4-(3-piperidin-1-yl-propoxy)phenyl]-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-4-methoxybenzoic acid, acetic anhydride and4-(3-piperidin-1-ylpropoxy)aniline monohydrochloride as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.43-1.48 (2H,m), 1.58-1.64 (4H,m),1.98-2.05 (2H,m), 2.24 (3H,s), 2.39-2.46 (4H,m), 2.51 (2H,t,J=7.6 Hz),3.93 (3H,s), 4.07 (2H,t,J=6.3 Hz), 7.07-7.01 (4H,m), 7.14 (2H,d,J=8.8Hz), 8.16 (1H,d,J=8.8 Hz)

Example 1707-methoxy-2-methyl-3-(4-{3-[(3S)-3-methyl-piperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was synthesized as a light yellow solid (m.p.:94-96°C.) by the method according to Example 165, using2-amino-4-methoxybenzoic acid, acetic anhydride and4-{3-[(3S)-3-methylpyridin-1-yl]propoxy}aniline monotosylate as startingmaterials, followed by recrystallization (ethyl acetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 0.83-0.92 (4H,m), 1.54-1.73 (5H,m),1.83-1.89 (1H,m), 1.98-2.06 (2H,m), 2.24 (3H,s), 2.50 (2H,t,J=7.6 Hz),2.83-2.91 (2H,m), 3.93 (3H,s), 4.07 (2H,t,J=6.3 Hz), 7.06-7.01 (4H,m),7.14 (2H,d,J=8.8 Hz), 8.16 (1H,d,J=8.8 Hz)

Example 1715-methoxy-2-methyl-3-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone(1) Manufacture of 4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}anilinemonotosylate

4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline was obtained as alight brown oily substance by the method according to Example 138, using(2R)-2-methylpyrrolidine hydrobromide, 3-bromopropanol and 4-nitrophenolas starting materials. The obtained oily substance was dissolved inethyl acetate, 1 Eq of a methanol solution of p-toluenesulfonic acidmonohydrate was added, and the target compound was obtained as acolorless solid by filtering off the solid produced.(2R)-2-methylpyrrolidine hydrobromide was manufactured by the methoddescribed in the literature (J. Org. Chem., 1989, Vol. 54, p. 209)

(2) Manufacture of5-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-6-methoxybenzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.11 (3H,d,J=5.9 Hz), 1.38-1.48 (1H,m),1.59-1.82 (2H,m), 1.89-2.33 (9H,m), 2.97-3.03 (1H,m), 3.17-3.22 (1H,m),3.95 (3H,s), 4.05-4.10 (2H,m), 6.87 (1H,d,J=8.3 Hz), 7.02 (2H,d,J=9.3Hz), 7.11 (2H,d,J=9.3 Hz), 7.24 (1H,d,J=8.3 Hz), 7.65 (1H,t,J=8.0 Hz)

NMR data for 4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}anilinemonotosylate used for manufacturing the compound of this example isshown below.

¹HNMR (400 MHz,CDCl₃/CD₃OD=5/1,δppm): 1.54 (3H,d,J=5.4 Hz), 1.89-2.06(2H,m), 2.18-2.43 (6H,m), 2.61 (4H,brs), 2.90-3.08 (1H,m), 3.21-3.26(1H,m), 3.44-3.52 (1H,m), 3.91-4.02 (3H,m), 6.67-6.72 (4H,m), 7.19(2H,d,J=8.3 Hz), 7.75 (2H,d,J=8.3 Hz)

Example 1726-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:106-108° C.)by the method according to Example 165, using 2-amino-5-methoxybenzoicacid, acetic anhydride and4-{3-[(2R)-3-methylpyridin-1-yl]propoxy}aniline monotosylate as startingmaterials, followed by recrystallization (ethyl acetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.11 (3H,d,J=5.9 Hz), 1.39-1.48 (1H,m),1.59-1.83 (2H,m), 1.89-2.07 (3H,m), 2.10-2.34 (6H,m), 2.97-3.04 (1H,m),3.17-3.22 (1H,m), 3.91 (3H,s), 4.07-4.12 (2H,m), 7.05 (2H,d,J=8.8 Hz),7.15 (2H,d,J=8.8 Hz), 7.36 (1H,dd,J=8.8, 2.9 Hz), 7.61 (1H,d,J=8.8 Hz),7.63 (1H,d,J=2.9 Hz)

Example 1737-methoxy-2-methyl-3-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-4-methoxybenzoic acid, acetic anhydride and4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.11 (3H,d,J=6.3 Hz), 1.39-1.48 (1H,m),1.58-1.83 (2H,m), 1.89-2.07 (3H,m), 2.10-2.51 (6H,m), 2.97-3.04 (1H,m),3.17-3.22 (1H,m), 3.93 (3H,s), 4.10-4.06 (2H,m), 7.01-7.06 (4H,m), 7.15(2H,d,J=8.8 Hz), 8.16 (1H,d,J=8.8 Hz)

Example 1743-[4-(3-azepan-1-ylpropoxy)phenyl-]-2,6-dimethyl-4(3H)-quinazolinone (1)Manufacture of 4-(3-azepan-1-ylpropoxy)aniline

The target compound was obtained by the method according to Example 138,using azepane, 3-bromopropanol and 4-nitrophenol as starting materials.

(2) Manufacture of3-[4-(3-azepan-1-ylpropoxy)phenyl]-2,6-dimethyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-5-methyl-benzoic acid, acetic anhydride and4-(3-azepan-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.62-1.64 (8H,m), 1.96-2.02 (2H,m), 2.24(3H,t,J=11.7 Hz), 2.48 (3H,t,J=11.7 Hz), 2.68 (6H,t,J=7.3 Hz), 4.07-4.09(2H,m), 7.04 (2H,dt,J=6.0, 3.6 Hz), 7.14 (2H,dt,J=12.2, 6.1 Hz), 7.57(2H,d,J=1.0 Hz), 8.05 (1H,s)

Example 1753-[4-(3-azepan-1-ylpropoxy)phenyl]-5-fluoro2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-6-fluorobenzoic acid, acetic anhydride and4-(3-azepan-1-yl-propoxy)aniline as starting materials. ¹HNMR (400MHz,CDCl₃,δppm): 1.61-1.63 (8H,m), 1.95-2.02 (2H,m), 2.22 (3H,t,J=10.0Hz), 2.67-2.68 (6H,m), 4.08 (2H,t,J=6.3 Hz), 7.03-7.15 (5H,m), 7.46(1H,d,J=8.3 Hz), 7.68 (1H,td,J=8.3, 5.4 Hz)

Example 1763-[4-(3-azepan-1-ylpropoxy)phenyl]-7-fluoro2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino 4-fluorobenzoic acid, acetic anhydride and4-(3-azepan-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.62-1.65 (8H,m), 1.95-2.02 (2H,m), 2.23(3H,t,J=14.6 Hz), 2.67-2.68 (6H,m), 4.08 (2H,t,J=6.3 Hz), 7.04-7.06(2H,m), 7.12-7.20 (3H,m), 7.31 (1H,dd,J=9.8, 2.4 Hz), 8.28 (1H,dd,J=8.8,5.9 Hz)

Example 177 3-[4-(3-azepan-1-ylpropoxy)phenyl]-5-methoxy-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-6-methoxybenzoic acid, acetic anhydride and4-(3-azepan-1-ylpropoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.63-1.66 (8H,m), 1.96-2.03 (2H,m), 2.20(3H,s), 2.68 (6H,d,J=6.8 Hz), 3.96 (3H,s), 4.08 (2H,t,J=6.3 Hz), 6.88(1H,d,J=7.8 Hz), 7.01-7.04 (2H,m), 7.10-7.13 (2H,m), 7.24 (1H,d,J=4.1Hz), 7.65 (1H,t,J=8.0 Hz)

Example 1783-[4-(3-azepan-1-ylpropoxy)phenyl]-6-methoxy-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-5-methoxybenzoic acid, acetic anhydride and4-(3-azepan-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.62-1.66 (8H,m), 1.96-2.03 (2H,m), 2.20(3H,s), 2.68-2.70 (6H,m), 3.91 (3H,s), 4.09 (2H,t,J=6.3 Hz), 7.05(2H,td,J=6.0, 3.6 Hz), 7.13-7.16 (2H,m), 7.36 (1H,dd,J=9.0, 3.2 Hz),7.60 (1H,s), 7.63 (1H,t,J=3.4 Hz)

Example 179

The title compound was obtained as white crystals, after treating with 1Eq of a ethyl acetate solution of 4N hydrochloric acid, andrecrystallizing (from ethanol/ethyl acetate), what had been synthesizedby the method according to Example 165, using 2-amino-6-methoxybenzoicacid, acetic anhydride and4-{3-[(3S)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃/CD₃OD=10/1,δppm): 1.01 (3H,d,J=6.3 Hz), 1.07-1.12(1H,m), 1.90-1.99 (2H,m), 2.25-2.52 (11H,m), 2.56-2.63 (1H,m), 3.20-3.24(2H,m), 3.51-3.54 (1H,m), 3.63-3.67 (1H,m), 4.15-4.18 (2H,m), 7.04(2H,d,J=8.3 Hz), 7.18 (2H,d,J=8.3 Hz), 7.60-7.64 (2H,m), 8.04 (1H,s)

Example 1803-[4-(3-azepan-1-ylpropoxy)phenyl]-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 4-aminonicotinic acid, acetic anhydride and4-(3-azepan-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.63 (4H,brs), 1.72 (4H,brs), 2.06-2.08(2H,m), 2.30 (3H,s), 2.76 (6H,brs), 4.10 (2H,t, J=6.3 Hz), 7.05-7.08(2H,m), 7.13-7.16 (2H,m), 7.49 (1H,d,J=2.9 Hz), 8.85 (1H,d,J=5.9 Hz),9.47 (1H,s)

Example 1812-methyl-3-(4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using anthranilic acid, acetic anhydride and4-{3-[(2R)-2-methyl-pyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.14 (3H,d,J=5.9 Hz), 1.43-1.55 (1H,m),1.69-1.85 (2H,m), 1.93-2.54 (9H,m), 2.99-3.07 (1H,m), 3.21-3.26 (1H,m),4.06-4.11 (2H,m), 7.05 (2H,d,J=8.8 Hz), 7.15 (2H,d,J=8.8 Hz), 7.46(1H,t,J=7.6 Hz), 7.67 (1H,d,J=7.8 Hz), 7.78-7.74 (1H,m), 8.27(1H,dd,J=8.0, 1.2 Hz)

Example 1822,5-dimethyl-3-[2-methoxy-4-[3-(1-piperidinyl)propoxy]phenyl]-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 63,using 2-amino-6-methylbenzoic acid, acetic anhydride,4-amino-3-methoxyphenol and 1-(3-bromopropyl) piperidine hydrobromide asstarting materials. 4-amino-3-methoxyphenol was manufactured by themethod described in the literature (J. Med. Chem., 1995, Vol. 38, p.2748).

¹HNMR (400 MHZ,CDCl₃,δppm): 1.42-1.48 (2H,m), 1.58-1.64 (4H,m),1.97-2.04 (2H,m), 2.19 (3H,s), 2.39-2.44 (4H,m), 2.50 (2H,t,J=7.2 Hz),2.82 (3H,s), 3.77 (3H,s), 4.06 (2H,t,J=6.4 Hz), 6.59-6.62 (2H,m), 7.08(1H,d,J=8.8 Hz), 7.19 (1H,d,J=8.0 Hz), 7.49 (1H,d,J=8.0 Hz), 7.58(1H,t,J=8.0 Hz)

Example 1832,5-dimethyl-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 63,using 2-amino-6-methyl benzoic acid, acetic anhydride,4-amino-3-methoxyphenol and 1-(3-bromopropyl)pyrrolidine hydrobromide asstarting materials.

¹HNMR (400 MHz, CDCl₃,δppm): 1.80-1.83 (4H,m), 2.01-2.07 (2H,m), 2.19(3H,s), 2.54-2.58 (4H,m), 2.66 (2H,t,J=7.2 Hz), 2.82 (3H,s), 3.77(3H,s), 4.08 (2H,t,J=6.4 Hz), 6.59-6.62 (2H,m), 7.08 (1H,d,J=8.8 Hz),7.19 (1H,d,J=8.0 Hz), 7.49 (1H,d,J=8.0 Hz), 7.58 (1H, t, J=8.0 Hz)

Example 1846-chloro-3-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using 5-amino-2-chloroisonicotinic acid, acetic anhydride,4-amino-3-methoxyphenol and 1-(3-bromopropyl)piperidine hydrobromide asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.48 (2H,m), 1.58-1.64 (4H,m),2.00-2.05 (2H,m), 2.25 (3H,s), 2.40-2.45 (4H,m), 2.51 (2H,t,J=7.2 Hz),3.77 (3H,s), 4.07 (2H,t,J=6.4 Hz), 6.61-6.64 (2H,m), 7.07 (1H,d,J=9.2Hz), 8.06 (1H,d,J=0.8 Hz), 8.90 (1H,d,J=0.8 Hz)

Example 1856-chloro-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using 5-amino-2-chloroisonicotinic acid, acetic anhydride,4-amino-3-methoxyphenol and 1-(3-bromopropyl)pyrrolidine hydrobromide asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.80-1.84 (4H,m), 2.02-2.09 (2H,m), 2.25(3H,s), 2.55-2.60 (4H,m), 2.68 (2H,t,J=7.2 Hz), 3.77 (3H,s), 4.10(2H,t,J=6.4 Hz), 6.61-6.64 (2H,m), 7.06 (1H,d,J=9.2 Hz), 8.06(1H,d,J=0.8 Hz), 8.89 (1H,d, J=0.8 Hz)

Example 1866-fluoro-3-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using 5-amino-2-fluoroisonicotinic acid, acetic anhydride,4-amino-3-methoxyphenol and 1-(3-bromopropyl)piperidine hydrobromide asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.51 (2H,m), 1.58-1.64 (4H,m),1.98-2.06 (2H,m), 2.25 (3H,s), 2.40-2.45 (4H,m), 2.51 (2H,t,J=7.2 Hz),3.78 (3H,s), 4.07 (2H,t,J=6.4 Hz), 6.61-6.64 (2H,m), 7.07 (1H,d,J=9.2Hz), 7.64-7.65 (1H,m), 8.76 (1H,s)

Example 1876-fluoro-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using 5-amino-2-fluoroisonicotinic acid, acetic anhydride,4-amino-3-methoxyphenol and 1-(3-bromopropyl)pyrrolidine hydrobromide asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.80-1.84 (4H,m), 2.02-2.09 (2H,m), 2.24(3H,s), 2.55-2.60 (4H,m), 2.67 (2H,t, J=7.2 Hz), 3.77 (3H,s), 4.10(2H,t,J=6.4 Hz), 6.61-6.64 (2H,m), 7.07 (1H,d, J=9.2 Hz), 7.64-7.66(1H,m), 8.76 (1H,s)

Example 1883-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]-pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-3-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 184 using a palladium charcoal catalyst in thepresence of triethylamine.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.42-1.48 (2H,m), 1.58-1.63 (4H,m),1.98-2.06 (2H,m), 2.27 (3H,s), 2.40-2.45 (4H,m), 2.51 (2H,t,J=7.2 Hz),3.77 (3H,s), 4.07 (2H,t,J=6.4 Hz), 6.61-6.64 (2H,m), 7.07 (1H,d,J=9.2Hz), 8.03 (1H,dd,J=0.8, 5.2 Hz), 8.66 (1H,d,J=5.2 Hz), 9.12 (1H,d,J=0.8Hz)

Example 1893-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methylpyrido[3,4-d]-pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 185 using a palladium charcoal catalyst in thepresence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.82-1.86 (4H,m), 2.04-2.11 (2H,m), 2.27(3H,s), 2.59-2.63 (4H,m), 2.70 (2H,t,J=7.2 Hz), 3.77 (3H,s), 4.10(2H,t,J=6.4 Hz), 6.61-6.64 (2H,m), 7.07 (1H,d,J=9.2 Hz), 8.03(1H,dd,J=0.8, 5.2 Hz), 8.66 (1H,d,J=5.2 Hz), 9.12 (1H,d, J=0.8 Hz)

Example 1903-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using 4-aminonicotinic acid, acetic anhydride, 4-amino-3-methoxyphenoland 1-(3-bromopropyl)piperidine hydrobromide as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.48 (2H,m), 1.58-1.63 (4H,m),1.98-2.06 (2H,m), 2.26 (3H,s), 2.40-2.45 (4H,m), 2.50 (2H,t,J=7.2 Hz),3.78 (3H,s), 4.07 (2H,t,J=6.4 Hz), 6.61-6.64 (2H,m), 7.08 (1H,d,J=8.8Hz), 7.48 (1H,dd,J=0.8, 5.6 Hz), 8.83 (1H,d,J=5.6 Hz), 9.47 (1H,d,J=0.8Hz)

Example 191 3-{3-bromo-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl5-(trifluoromethyl)-4(3H)-quinazolinone (1) Manufacture of4-amino-2-bromophenol

The target compound was obtained by reducing 2-bromo-4-nitrophenol withiron in a mixed solution of methanol and ammonium chloride aqueoussolution. 2-bromo-4-nitrophenol was manufactured by the method describedin the literature (J. Org. Chem., Vol. 62, 1997, p. 4504).

(2) Manufacture of3-{3-bromo-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-5-(trifluoromethyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 63,using 2-amino-6-(trifluoromethyl)benzoic acid, acetic anhydride,4-amino-2-bromophenol and 1-(3-bromopropyl)pyrrolidine hydrobromide asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.81 (4H,m), 2.10 (2H,m), 2.28 (3H,s), 2.57(4H,m), 2.70 (2H,m), 4.13 (2H,m), 7.05 (1H,d,J=8.8 Hz), 7.17 (1H,d,J=8.8 Hz), 7.46 (1H,s), 7.83 (1H,d,J=8.0 Hz), 7.88 (2H,d,J=8.0 Hz)

Example 192 6-chloro-3-[2-fluoroethoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1) Manufacture of6-chloro-3-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidine-4(3H)-one

6-chloro-3-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 184 (143 mg, 0.32 mmol) was dissolved inmethylene chloride (3 mL), boron tribromide (1M methylene chloridesolution, 3.2 mmol) was added on an ice bath, stirred at roomtemperature for 15 hours, and stirred at 40° C. for 3 hours. Saturatedcarbonated water was added to stop the reaction, the mixture wasextracted with ethyl acetate, and dried with anhydrous sodium sulfate.The product was purified by silica gel column chromatography(chloroform/methanol=20/1), and the target compound (49 mg, 35%) wasobtained as a light yellow solid.

¹HNMR (400 MHz,CDCl₃,δppm): 1.38-1.43 (2H,m), 1.52-1.59 (4H,m),2.01-2.07 (2H,m), 2.32 (3H,s), 2.51-2.57 (4H,m), 2.64-2.80 (2H,m), 3.99(2H,t,J=6.4 Hz), 6.41-6.45 (2H,m), 6.99 (1H,d,J=8.4 Hz), 8.05(1H,d,J=0.8 Hz), 8.90 (1H,d, J=0.8 Hz)

(2) Manufacture of6-chloro-3-[2-fluoroethoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

6-chloro-3-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]-pyrimidin-4(3H)-one(10 mg), 2-fluoroethyl tosylate (7.6 mg) and potassium carbonate (16 mg)were mixed in dimethylformamide (2 mL) and stirred at 80° C. for 10hours. Distilled water was added, the mixture extracted with ethylacetate, and dried with anhydrous sodium sulfate. The product waspurified by silica gel thin layer chromatography(chloroform/methanol=10/1), and the title compound (8.5 mg, 77%) wasobtained as a colorless solid.

¹HNMR (40 MHz,CDCl₃,δppm): 1.42-1.48 (2H,m), 1.58-1.64 (4H,m), 1.98-2.05(2H,m), 2.28 (3H,s), 2.40-2.45 (4H,m), 2.50 (2H,t,J=7.2 Hz), 4.07(2H,t,J=6.4 Hz) 4.10-4.36 (2H,m), 4.49-4.52 (1H,m), 4.61-4.64 (1H,m),6.64 (1H,d,J=2.4 Hz), 6.67 (1H,dd,J=2.4, 8.4 Hz), 7.09 (1H,d,J=8.4 Hz),8.05 (1H,s), 8.90 (1H,s)

Example 1932,5-dimethyl-3-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-4(3H)-quinazolinone

2,5-dimethyl-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized in Example 182 was demethylated using the method accordingto Example 192-(1), and the title compound was thus obtained.

¹HNMR (400 MHz,CDCl₃,δppm): 1.38-1.45 (2H,m), 1.55-1.61 (4H,m),1.97-2.04 (2H,m), 2.27 (3H,s), 2.43-2.52 (4H,m), 2.55-2.64 (2H,m), 2.80(3H,s), 3.92-3.98 (2H,m), 6.44-6.48 (2H,m), 6.99 (1H,d,J=8.0 Hz), 7.16(1H,d,J=8.0 Hz), 7.49 (1H,d,J=8.0 Hz), 7.56 (1H,t,J=8.0 Hz)

Example 1942,5-dimethyl-3-{2-fluoroethoxy-4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example192-(2) using2,5-dimethyl-3-{2-hydroxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinonesynthesized in Example 193, and 2-fluoroethyl tosylate as startingmaterials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.42-1.49 (2H,m), 1.59-1.65 (4H,m),1.98-2.06 (2H,m), 2.22 (3H,s), 2.40-2.49 (4H,m), 2.52 (2H,t,J=7.2 Hz),2.82 (3H,s), 4.05 (2H,t,J=6.4 Hz), 4.10-4.33 (2H,m), 4.50-4.54 (1H,m),4.62-4.66 (1H,m), 6.62 (1H,d,J=2.4 Hz), 6.65 (1H,dd,J=2.4, 8.4 Hz), 7.10(1H,d,J=8.4 Hz), 7.20 (1H,d,J=8.0 Hz), 7.51 (1H,d,J=8.0 Hz), 7.58 (1H,t, J=8.0 Hz)

Example 1953-{2-fluoroethoxy-4-[3-(1-piperidinyl)propoxy]phenyl}-2-methylpyrido[3,4-d]-pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-3-{2-fluoroethoxy-[3-(1-piperidinyl)propoxy]phenyl}-2-methylpyrido[3,4-]pyrimidin-(3H)-onesynthesized in Example 192 using a palladium charcoal catalyst in thepresence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.49 (2H,m), 1.58-1.64 (4H,m),1.98-2.06 (2H,m), 2.29 (3H,s), 2.40-2.47 (4H,m), 2.51 (2H,t,J=7.2 Hz),4.07 (2H,t, J=6.4 Hz), 4.10-4.36 (2H,m), 4.49-4.52 (1H,m), 4.61-4.64(1H,m), 6.64 (1H,d,J=2.4 Hz), 6.67 (1H,dd,J=2.4, 8.4 Hz), 7.10(1H,d,J=8.4 Hz), 8.02 (1H,dd,J=0.8, 5.2 Hz), 8.66 (1H,d,J=5.2 Hz), 9.12(1H,d,J=0.8 Hz)

Example 1963-{2-fluoroethoxy-4-[3-(1-piperidinyl)propoxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-(3H)-one

The title compound was obtained by the method according to Example 192,using3-{2-methoxy-4-[3-(1-piperidinyl)propoxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-onesynthesized in Example 190 and 2-fluoroethyl tosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.42-1.49 (2H,m), 1.58-1.64 (4H,m), 2.01-2.05(2H,m), 2.29 (3H,s), 2.41-2.47 (4H,m), 2.52 (2H,t,J=7.2 Hz), 4.07(2H,t,J=6.4 Hz), 4.10-4.38 (2H,m), 4.50-4.53 (1H,m), 4.62-4.64 (1H,m),6.64 (1H,d,J=2.4 Hz), 6.67 (1H,dd,J=2.4, 8.4 Hz), 7.11 (1H,d,J=8.4 Hz),7.49 (1H,dd,J=0.8, 5.6 Hz), 8.84 (1H,d,J=5.6 Hz), 9.46 (1H,d,J=0.8 Hz)

Example 1973-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(1) Manufacture of6-chloro-3-(4-hydroxyphenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The target compound was obtained by the method according to Example1-(1) and -(2), using 5-amino-2-chloroisonicotinic acid, aceticanhydride and 4-aminophenol as starting materials.

(2) Manufacture of3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

6-chloro-3-(4-hydroxyphenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(300 mg, 1.04 mmol) was dissolved in dry methanol (15 mL) in a currentof nitrogen, sodium methoxide (7 mmol) was added and the mixture washeated under reflux for 20 hours. After leaving to cool, acetic acid wasadded and the solvent was distilled off under reduced pressure.Distilled water was added to the residue, the solid precipitate wasfiltered off, and the title compound (259 mg, 88%) was thus obtained asa lavender color solid.

¹HNMR (400 MHZ,CDCl₃/CD₃OD=5/1,δppm) 2.21 (3H,s), 3.99 (3H,s), 6.94(2H,d,J=8.8 Hz), 7.01 (2H,d,J=8.8 Hz), 7.40 (1H,s), 8.71 (1H,s)

Example 1982-ethyl-3-(4-hydroxyphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 197,using 5-amino-2-chloroisonicotinic acid, propionic anhydride,4-aminophenol and sodium methoxide as starting materials.

¹HNMR (400 MHz,CDCl₃/CD₃OD=5/1,δppm) 1.21 (3H,t,J=7.6 Hz), 2.47(2H,q,J=7.6 Hz), 4.03 (3H,s), 6.98 (2H,d,J=8.8 Hz), 7.04 (2H,d,J=8.8Hz), 7.44 (1H,s), 8.79 (1H,s)

Example 1996-methoxy-2-methyl-3-[4-(3-piperidin-1-ylpropoxy)phenyl]pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was synthesized as a white solid (m.p.:145-147° C.)by the method according to Example 63, using3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 197 and 1-(3-bromopropyl)pyridine hydrobromide asstarting materials, followed by recrystallization (ethyl acetate/diethylether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.43-1.49 (2H,m), 1.58-1.64 (4H,m),2.00-2.06 (2H,m), 2.24 (3H,s), 2.40-2.47 (4H,m), 2.52 (2H,t,J=7.2 Hz),4.03 (3H,s), 4.07 (2H,t,J=6.4 Hz), 7.05 (2H,d,J=9.2 Hz), 7.13(2H,d,J=9.2 Hz), 7.45 (1H,d,J=0.8 Hz), 8.75 (1H,d,J=0.8 Hz)

Example 2006-methoxy-2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]pyrido[3,4-d]-pyrimidin-4(3H)-one

The title compound was synthesized as a white solid (m.p.:123-126° C.)by the method according to Example 63, using3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 197 and 1-(3-bromopropyl)pyrrolidine hydrobromideas starting materials, followed by recrystallization (ethylacetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.80-1.84 (4H,m), 2.02-2.08 (2H,m), 2.23(3H,s), 2.55-2.61 (4H,m), 2.68 (2H,t,J=7.2 Hz), 4.03 (3H,s), 4.10(2H,t,J=6.4 Hz), 7.05 (2H,d,J=9.2 Hz), 7.13 (2H,d,J=9.2 Hz), 7.45(1H,d,J=0.8 Hz), 8.75 (1H,d,J=0.8 Hz)

Example 2012-ethyl-6-methoxy-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using2-ethyl-3-(4-hydroxyphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 198 and 1-(3-bromopropyl)piperidine hydrobromideas starting materials.

¹HNMR (400 MHz, CDCl₃,δppm): 1.21 (3H,t,J=7.6 Hz), 1.43-1.49 (2H,m),1.58-1.64 (4H,m), 2.00-2.06 (2H,m), 2.40-2.58 (8H,m), 4.01-4.08 (5H,m),7.05 (2H,d,J=9.2 Hz), 7.13 (2H,d,J=9.2 Hz), 7.45 (1H,s), 8.77 (1H,s)

Example 2022-ethyl-6-methoxy-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl)-pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using 2-ethyl3-(4-hydroxyphenyl)-6-methoxypyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 198 and 1-(3-bromopropyl)pyrrolidine hydrobromideas starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.22 (3H,t,J=7.6 Hz), 1.82-1.86 (4H,m),2.04-2.11 (2H,m), 2.44 (2H,q,J=7.2 Hz), 2.58-2.63 (4H,m), 2.70(2H,t,J=7.2 Hz), 4.04 (3H,s), 4.10 (2H,t,J=6.4 Hz), 7.05 (2H,d,J=9.2Hz), 7.13 (2H,d,J=9.2 Hz), 7.45 (1H,s), 8.79 (1H,s)

Example 2036-methoxy-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(1) Manufacture of3-(4-hydroxy-2-methoxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The target compound was obtained by the method according to Example 197,using 5-amino-2-chloroisonicotinic acid, acetic anhydride,4-amino-3-methoxyphenol and sodium methoxide as starting materials.

(2) Manufacture of6-methoxy-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 63,using3-(4-hydroxy-2-methoxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-oneand 1-(3-bromopropyl)pyrrolidine hydrobromide as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.80-1.84 (4H,m), 2.02-2.07 (2H,m), 2.20(3H,s), 2.55-2.60 (4H,m), 2.68 (2H,t,J=7.2 Hz), 3.77 (3H,s), 4.02(3H,s), 4.09 (2H,t,J=6.4 Hz), 6.60-6.63 (2H,m), 7.07 (1H,d,J=8.8 Hz),7.45 (1H,s), 8.75 (1H,s)

Example 2046-bromo-3-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone(1) Manufacture of6-bromo-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The target compound was obtained by the method according to Example 63,using 2-amino-5-bromobenzoic acid, acetic anhydride,4-amino-3-methoxyphenol and 1-(3-bromopropyl)pyrrolidine hydrobromide asstarting materials.

(2) Manufacture of6-bromo-3-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 192using6-bromo-3-{2-methoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinoneand 2-fluoroethyl tosylate as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.82-1.86 (4H,m), 2.05-2.12 (2H,m), 2.23(3H,s), 2.62-2.66 (4H,m), 2.72 (2H,t,J=7.2 Hz), 4.10 (2H,t,J=6.4 Hz),4.12-4.34 (2H,m), 4.50 (1H,t,J=4.0 Hz), 4.62 (1H,t,J=4.0 Hz), 6.64-6.68(2H,m), 7.09 (1H,d,J=8.8 Hz), 7.55 (1H,d,J=8.4 Hz), 7.82 (1H,dd,J=8.8,2.4 Hz), 8.37 (1H,d,J=2.4 Hz

Example 2056-ethoxycarbonyl-3-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

6-bromo-3-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinonesynthesized in Example 204 (37 mg), palladium(II) acetate (2 mg), dppf(1,1′-bis(diphenylphosphino)ferrocene) (8.2 mg) and triethylamine (22mg) were mixed in ethanol (5 mL), and the atmosphere in the system wasreplaced by carbon monoxide. The mixture was then heated under reflux inthe carbon monoxide atmosphere for 2 days. Ethyl acetate was added tothe reaction liquid, and the solid precipitate was filtered off. Thefiltrate was concentrated, purified by silica gel thin layerchromatography (chloroform/methanol=10/1), and the title compound (23mg, 63%) was thus obtained as a light gray solid.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41 (3H,t,J=7.2 Hz), 1.60-1.81 (4H,m),2.17-2.21 (4H,m), 2.27 (3H,s), 2.43-2.50 (2H,m), 3.23-3.32 (2H,m),4.13-4.38 (4H,m), 4.41 (2H,q, J=7.2 Hz), 4.50-4.53 (1H,m), 4.62-4.64(1H,m), 6.65 (1H,dd,J=2.4, 8.8 Hz), 6.70 (1H,d,J=2.4 Hz), 7.13(1H,d,J=8.8 Hz), 7.71 (1H,d,J=8.8 Hz), 8.38 (1H,dd,J=2.4, 8.8 Hz), 8.93(1H,d,J=2.4 Hz)

Example 2063-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]-phenyl}-6-methoxycarbonyl-2-methyl4(3H)-quinazolinone

6-ethoxycarbonyl-3-{2-fluoroethoxy-4-[3-(1-pyrrolidinyl)propoxy]-phenyl}-2-methyl-4(3H)-quinazolinonesynthesized in Example 205 was treated by sodium methoxide in drymethanol, and the title compound was thus obtained.

¹HNMR (400 MHz, CDCl₃,δppm): 1.82-1.88 (4H,m), 2.05-2.12 (2H,m), 2.27(3H,s), 2.62-2.66 (4H,m), 2.72 (2H,t,J=7.3 Hz), 3.95 (3H,s), 4.10(2H,t,J=6.3 Hz), 4.17-4.34 (2H,m), 4.50 (1H,t,J=4.1 Hz), 4.62(1H,t,J=4.1 Hz), 6.65-6.68 (2H,m), 7.11 (1H,d,J=8.3 Hz), 7.70(1H,d,J=8.3 Hz), 8.37 (1H,dd,J=8.5, 2.2 Hz), 8.93 (1H,d,J=2.0 Hz)

Example 2073-{3-fluoro-4-[3-(1-piperidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 63,using anthranilic acid, acetic anhydride, 4-amino-2-fluorophenol and1-(3-bromopropyl) piperidine hydrobromide as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.43-1.48 (2H,m), 1.57-1.63 (4H,m),2.02-2.09 (2H,m), 2.28 (3H,s), 2.39-2.45 (4H,m), 2.52 (2H,t,J=7.1 Hz),4.16 (2H,t,J=6.3 Hz), 6.96-7.06 (2H,m), 7.13 (1H,t,J=8.8 Hz), 7.49-7.45(1H,m), 7.67 (1H,d,J=8.3 Hz), 7.75-7.79 (1H,m), 8.27 (1H,dd,J=7.8, 1.5Hz)

Example 208 3-{2-fluoro-4-[3-(1-piperidinyl)propoxy]phenyl}-2-methyl4(3H)-quinazolinone

The title compound was obtained by the method according to Example 63,using anthranilic acid, acetic anhydride, 4-amino-3-fluorophenol and1-(3-bromopropyl)piperidine hydrobromide as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.42-1.49 (2H,m), 1.58-1.63 (4H,m),1.98-2.04 (2H,m), 2.29 (3H,s), 2.38-2.44 (4H,m), 2.49 (2H,t,J=7.3 Hz),4.06 (2H,t,J=6.3 Hz), 6.82-6.86 (2H,m), 7.17 (1H,t,J=8.5 Hz), 7.45-7.49(1H,m), 7.68 (1H,d,J=7.3 Hz), 7.75-7.79 (1H,m), 8.27 (1H,dd,J=8.0, 1.2Hz)

Example 2092-methyl-3-{3-methyl-4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 63,using anthranilic acid, acetic anhydride, 4-amino-2-methylphenol and1-(3-bromopropyl) piperidine hydrobromide as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.43-1.49 (2H,m), 1.59-1.64 (4H,m),2.01-2.08 (2H,m), 2.26 (3H,s), 2.27 (3H,s), 2.40-2.46 (4H,m), 2.51-2.55(2H,m), 4.03-4.11 (2H,m), 6.94 (1H,d,J=8.8 Hz), 7.00-7.03 (2H,m), 7.45(1H,td,J=7.6, 1.3 Hz), 7.67 (1H,d,J=7.3 Hz), 7.73-7.78 (1H,m), 8.27(1H,dd,J=7.8, 1.0 Hz)

Example 2102-methyl-3-{2-methyl-4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 63,using anthranilic acid, acetic anhydride, 4-amino-3-methyl phenol and1-(3-bromopropyl)piperidine hydrobromide as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.43-1.48 (2H,m), 1.58-1.64 (4H,m),1.98-2.05 (2H,m), 2.08 (3H,s), 2.20 (3H,s), 2.39-2.46 (4H,m), 2.50(2H,t,J=7.4 Hz), 4.05 (2H,t,J=6.3 Hz), 6.92-6.86 (2H,m), 7.04(1H,d,J=8.3 Hz), 7.45-7.49 (1H,m), 7.68 (1H,d,J=7.8 Hz), 7.75-7.79(1H,m), 8.28 (1H,dd,J=8.0, 1.7 Hz)

Example 2113-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]-2-methoxyphenyl}-2,5-dimethyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 88,using 2-amino-6-methylbenzoic-acid, acetic anhydride,4-amino-3-methoxyphenol, t-butyl-4-hydroxypiperidine-1-carboxylate andcyclobutanone as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.77 (2H,m), 1.84-1.95 (4H,m),2.01-2.10 (4H,m), 2.17-2.25 (5H,m), 2.59-2.68 (2H,m), 2.73-2.81 (1H,m),2.83 (3H,s), 3.77 (3H,s), 4.33-4.41 (1H,m), 6.58-6.63 (2H,m), 7.07(1H,d,J=8.4 Hz), 7.20 (1H,d,J=8.4 Hz), 7.50 (1H,d,J=8.4 Hz), 7.58(1H,t,J=8.4 Hz)

Example 2123-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]phenyl}-6-methoxy-2-methylpyrido[3,4-d]-pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 88,using3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 197, t-butyl-4-hydroxy piperidine-1-carboxylateand cyclobutanone as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.77 (2H,m), 1.84-1.95 (4H,m),2.01-2.10 (4H,m), 2.17-2.24 (2H,m), 2.25 (3H,s), 2.61-2.69 (2H,m),2.73-2.81 (1H,m), 4.04 (3H,s), 4.37-4.43 (1H,m), 7.05 (2H,d,J=8.8 Hz),7.14 (2H,d,J=8.8 Hz), 7.46 (1H,s), 8.77 (1H,s)

Example 2133-{4-[(1-cyclopentyl-piperidin-4-yl)oxy]phenyl}-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 88,using3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 197, t-butyl-4-hydroxy piperidine-1-carboxylateand cyclopentanone as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.40-1.49 (2H,m), 1.52-1.62 (2H,m), 1.67-1.75(2H,m), 1.85-1.95 (4H,m), 2.03-2.13 (2H,m), 2.24 (3H,s), 2.34-2.42(2H,m), 2.53-2.58 (1H,m), 2.80-2.86 (2H,m), 4.03 (3H,s), 4.36-4.41(1H,m), 7.05 (2H,d,J=8.8 Hz), 7.14 (2H,d, J=8.8 Hz), 7.45 (1H,s), 8.75(1H,s)

Example 2146-chloro-3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-methoxyphenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 88,using 5-amino-2-chloroisonicotinic-acid, acetic anhydride,4-amino-3-methoxyphenol and t-butyl-4-hydroxypiperidine-1-carboxylateand cyclobutanone as starting materials.

¹HNMR (40 MHz,CDCl₃,δppm): 1.64-1.77 (2H,m), 1.84-1.95 (4H,m), 2.01-2.10(4H,m), 2.17-2.25 (5H,m), 2.59-2.68 (2H,m), 2.73-2.82 (1H,m), 3.77(3H,s), 4.36-4.42 (1H,m), 6.586.63 (2H,m), 7.07 (1H,d,J=8.4 Hz), 8.06(1H,s), 8.90 (1H,s)

Example 2153-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]-2-methoxyphenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 88,using 4-aminonicotinic acid, acetic anhydride, 4-amino-3-methoxyphenol,t-butyl-4-hydroxypiperidine-1-carboxylate and cyclobutanone as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.74 (2H,m), 1.82-1.95 (4H,m),2.01-2.10 (4H,m), 2.17-2.24 (2H,m), 2.26 (3H,s), 2.62-2.69 (2H,m),2.73-2.80 (1H,m), 3.77 (3H,s), 4.36-4.41 (1H,m), 6.59-6.63 (2H,m), 7.07(1H,d,J=8.4 Hz), 7.48 (1H,d,J=5.6 Hz), 8.83 (1H,d,J=5.6 Hz), 9.46 (1H,s)

Example 2163-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]-3-fluorophenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 88,using anthranilic acid, acetic anhydride, 4-amino-2-fluorophenol,t-butyl-4-hydroxypiperidine-1-carboxylate and cyclobutanone as startingmaterials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.64-1.75 (2H,m), 1.85-1.96 (4H,m),1.99-2.10 (4H,m), 2.16-2.26 (2H,m), 2.28 (3H,s), 2.59-2.70 (2H,m),2.72-2.81 (1H,m), 4.37-4.45 (1H, m), 6.95-6.98 (1H,m), 7.03(1H,dd,J=10.7, 2.4 Hz), 7.12 (1H,t,J=8.8 Hz), 7.46-7.50 (1H,m), 7.67(1H,d,J=7.3 Hz), 7.78 (1H,td,J=7.7, 1.6 Hz), 8.26 (1H,dd,J=7.8, 1.5 Hz)

Example 2173-{4-[(1-cyclopentyl-piperidin-4-yl)oxy]-3-fluorophenyl}-2-methyl4(3H)-quinazolinone

The title compound was obtained by the method according to Example 88,using anthranilic acid, acetic anhydride, 4-amino-2-fluorophenol,t-butyl-4-hydroxypiperidine-1-carboxylate and cyclopentanone as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.39-1.49 (2H,m), 1.53-1.61 (2H,m),1.68-1.74 (2H,m), 1.86-1.98 (4H,m), 2.03-2.11 (2H,m), 2.28 (3H,s),2.35-2.46 (2H,m), 2.52-2.59 (1H,m), 2.87-2.79 (2H,m), 4.39-4.44 (1H,m),6.95-6.98 (1H,m), 7.03 (1H,dd,J=10.7, 2.4 Hz), 7.13 (1H,t,J=8.5 Hz),7.48 (1H,t,J=8.0 Hz), 7.67 (1H,d,J=7.8 Hz), 7.76-7.80 (1H,m), 8.27(1H,dd,J=7.8, 1.5 Hz)

Example 2183-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]-2-fluorophenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 88,using anthranilic acid, acetic anhydride, 4-amino-3-fluorophenol,t-butyl-4-hydroxypiperidine-1-carboxylate and cyclobutanone as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.75 (2H,m), 1.84-1.95 (4H,m),2.01-2.10 (4H,m), 2.17-2.27 (2H,m), 2.29 (3H,s), 2.59-2.67 (2H,m),2.73-2.81 (1H,m), 4.39-4.34 (1H,m), 6.80-6.85 (2H,m), 7.17 (1H,t,J=8.8Hz), 7.46-7.49 (1H,m), 7.68 (1H,d,J=8.3 Hz), 7.75-7.79 (1H,m), 8.27(1H,dd,J=8.0, 1.2 Hz)

Example 2193-{4-[(1-cyclopentyl-piperidin-4-yl)oxy]-2-fluorophenyl}-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 88,using anthranilic acid, acetic anhydride, 4-amino-3-fluorophenol,t-butyl-4-hydroxypiperidine-1-carboxylate and cyclopentanone as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.41-1.49 (2H,m), 1.53-1.60 (2H,m),1.68-1.75 (2H,m), 1.86-1.94 (4H,m), 2.03-2.11 (2H,m), 2.29 (3H,s),2.37-2.45 (2H,m), 2.53-2.60 (1H,m), 2.79-2.85 (2H,m), 4.40-4.34 (1H,m),6.80-6.85 (2H,m), 7.17 (1H,t,J=8.8 Hz), 7.45-7.49 (1H,m), 7.68(1H,d,J=7.8 Hz), 7.75-7.79 (1H,m), 8.27 (1H,dd,J=8.3, 1.5 Hz)

Example 2202-methyl-3-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]-2-methylphenyl}-4(3H)-quinazolinonehydrochloride

The title compound was obtained by the method according to Example 88,using anthranilic acid, acetic anhydride, 4-amino-3-methylphenol,t-butyl-4-hydroxypiperidine-1-carboxylate and cyclobutanone as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.73-1.85 (2H,m), 2.12 (3H,s), 2.17-2.30(4H,m), 2.69-2.90 (7H,m), 3.34-3.45 (4H,m), 4.78-4.83 (1H,m), 6.93-7.00(2H,m), 7.23-7.15 (1H,m), 7.70 (1H,t,J=7.6 Hz), 7.95 (1H,t,J=7.3 Hz),8.32 (1H,d,J=7.8 Hz), 8.41 (1H,d,J=7.3 Hz)

Example 2212-methyl-3-{4-[(1-cyclopentyl-piperidin-4-yl)oxy]-2-methylphenyl}-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 88,using anthranilic acid, acetic anhydride, 4-amino-3-methylphenol,t-butyl-4-hydroxypiperidine-1-carboxylate and cyclopentanone as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.40-1.49 (2H,m), 1.53-1.59 (2H,m),1.67-1.74 (2H,m), 1.85-1.93 (4H,m), 2.02-2.09 (5H,m), 2.20 (3H,s),2.35-2.43 (2H,m), 2.51-2.58 (1H,m), 2.79-2.86 (2H,m), 4.34-4.40 (1H,m),6.87 (1H,dd,J=8.8, 2.9 Hz), 6.92 (1H,d,J=2.4 Hz), 7.04 (1H,d,J=8.3 Hz),7.45-7.49 (1H,m), 7.68 (1H,d,J=7.3 Hz), 7.75-7.80 (1H,m), 8.29(1H,dd,J=8.0, 1.2 Hz)

Example 2223-{4-[(1-cyclopentyl-piperidin-4-yl)oxy]-2-(2-fluoroethoxy)phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 192,using3-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]-2-methoxyphenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-onesynthesized in Example 221 and 2-fluoroethyl tosylate which were used asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.77 (2H,m), 1.84-1.95 (4H,m),2.01-2.11 (4H,m), 2.15-2.23 (2H,m), 2.29 (3H,s), 2.61-2.69 (2H,m),2.71-2.80 (1H,m), 4.10-4.34 (2H,m), 4.35-4.41 (1H,m), 4.50-4.52 (1H,m),4.62-4.64 (1H,m), 6.64-6.67 (2H,m), 7.10 (1H,d,J=8.4 Hz), 7.48(1H,d,J=5.6 Hz), 8.84 (1H,d,J=5.6 Hz), 9.46 (1H,s)

Example 2233-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoroethoxy-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 192,using3-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinonesynthesized in Example 105 and 2-fluoroethyl tosylate as startingmaterials. ¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.76 (2H m), 1.84-1.96(4H,m), 2.01-2.10 (4H,m), 2.18-2.25 (5H,m), 2.61-2.69 (2H,m), 2.73-2.81(1H,m), 4.28-4.31 (1H,m), 4.36-4.40 (2H,m), 4.75-4.77 (1H,m), 4.87-4.89(1H,m), 6.89 (1H,d,J=8.4 Hz), 7.01 (2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8Hz), 8.29 (1H,d,J=8.0 Hz), 7.64 (1H,t,J=8.0 Hz)

Example 2246-chloro-3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-(2-fluoroethoxy)phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 192,using 6-chloro-3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-methoxyphenyl}-2-methylpyrido[3.,4-d]pyrimidin-4(3H)-onesynthesized in Example 220 and 2-fluoroethyl tosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm) 1.67-1.75 (2H,m), 1.84-1.95 (4H,m), 2.01-2.10(4H,m), 2.15-2.24 (2H,m), 2.28 (3H,s), 2.61-2.69 (2H,m), 2.73-2.81(1H,m), 4.10-4.32 (2H,m), 4.34-4.40 (1H,m), 4.49-4.51 (1H,m), 4.61-4.63(1H,m), 6.64-6.66 (2H,m), 7.08 (1H,d,J=8.4 Hz), 8.05 (1H,s), 8.90 (1H,s)

Example 2253-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]-2-(2-fluoroethoxyphenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-(2-fluoroethoxy)phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 230, using palladium charcoal as catalyst in thepresence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.66-1.77 (2H,m), 1.84-1.95 (4H,m),2.01-2.10 (4H,m), 2.15-2.24 (2H,m), 2.29 (3H,s), 2.61-2.69 (2H,m),2.72-2.81 (1H,m), 4.10-4.33 (2H,m), 4.35-4.41 (1H,m), 4.49-4.51 (1H,m),4.61-4.63 (1H,m), 6.64-6.67 (2H,m), 7.10 (1H,d,J=8.4 Hz), 8.02(1H,dd,J=1.2, 5.6 Hz), 8.66 (1H,d,J=5.6 Hz), 9.12 (1H,d,J=1.2 Hz)

Example 2263-{(2-[(1-cyclobutylpiperidin-4-yl)oxy]-pyrimidin-5-yl}-2-methyl-5-(trifluoromethyl)-4(3H)-quinazolinone(1) Manufacture oft-butyl-4-[(5-nitroglycerine-pyrimidin-2-yl)oxy]piperidine-1-carboxylate

2-chloro-5-nitroglycerine-pyrimidine (80 mg, 0.5 mmol),t-butyl-4-hydroxypiperidine-1-carboxylate (100 mg, 0.5 mmol) and cesiumfluoride (114 mg, 0.75 mmol) were mixed in dimethylformamide, andstirred at room temperature for 12 hours. The solvent was distilled offunder reduced pressure, the product was purified by silica gel columnchromatography (hexane/ethyl acetate=10/0-3/7), and the target compound(61 mg, 38%) was thus obtained as a light yellow solid.

(2) Manufacture oft-butyl-4-[(5-aminopyrimidin-2-yl)oxy]piperidine-1-carboxylate

t-butyl-4-[(5-nitroglycerine-pyrimidin-2-yl)oxy]piperidine-1-carboxylate(500 mg, 1.54 mmol) was dissolved in a mixed solvent of methanol (10 mL)and tetrahydrofuran (10 mL), and palladium charcoal (10%, 200 mg) wasadded in a current of nitrogen. The atmosphere in the system wasreplaced by hydrogen, and the mixture stirred at room temperature for 3hours. The reaction liquid was filtered through cerite, the filtrate wasconcentrated, dried, and the target compound (439 mg, 97%) was thusobtained.

(3) 2-methyl-3-[2-(piperidin-4-yl-oxy)pyrimidine5-yl]-5-(trifluoromethyl)-4(3H)-quinazolinone

2-methyl-5-(trifluoromethyl)-4H-3,1-benzoxadin-4-one (78 mg, 0.34 mmol)and t-butyl-4-[(5-amino-pyrimidin-2-yl)oxy]piperidine-1-carboxylate (100mg, 0.34 mmol) were dissolved in acetic acid (2 mL), and stirred at 130°C. for 6 hours. Acetic acid was distilled off under reduced pressure, 1Nsodium hydroxide aqueous solution was added, and the mixture extractedwith ethyl acetate. The product was dried with anhydrous sodium sulfate,and concentrated to obtain the target compound (112 mg, 81%) as a brownamorphous solid.

(4) Manufacture of3-{2-[(1-cyclobutylpiperidin-4-yl)oxy]pyrimidin-5-yl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example88-(3), using2-methyl-3-[2-(piperidin-4-yl-oxy)pyrimidin-5-yl]-5-(trifluoromethyl)-4(3H)-quinazolinoneand cyclobutanone as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.64-1.75 (2H,m), 1.86-2.01 (4H,m),2.01-2.15 (4H,m), 2.17-2.28 (2H,m), 2.32 (3H,s), 2.64-2.74 (2H,m),2.74-2.81 (1H,m), 5.10-5.18 (1H,brs), 7.83-7.93 (3H,m), 8.46 (2H,s)

Example 2273-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]phenyl}-5-methoxy-2-propyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-methoxybenzoic acid, butyric anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline as starting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 0.86 (3H,t,J=7.2 Hz), 1.64-1.75 (4H,m),1.83-1.95 (4H,m), 2.01-2.11 (4H,m), 2.14-2.22 (2H,m), 2.36-2.40 (2H,m),2.60-2.70 (2H,m), 2.72-2.80 (1H,m), 3.94 (3H,s), 4.35-4.42 (1H,m), 6.86(1H,dd,J=0.8, 8.4 Hz), 7.00 (2H,d,J=8.8 Hz), 7.10 (2H,d, J=8.8 Hz), 7.26(1H,dd,J=0.8, 8.0 Hz), 7.64 (1H,t,J=8.0 Hz)

Example 2283-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:171-173° C.)by the method according to Example 94, using 2-amino-5-methoxybenzoicacid, acetic anhydride and 4-[(1-cyclobutylpiperidin-4-yl)oxy]anilinemonotosylate as starting materials, followed by recrystallization (ethylacetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.64-1.74 (2H,m), 1.85-1.96 (4H,m),2.01-2.13 (4H,m), 2.15-2.24 (2H,m), 2.23 (3H,s), 2.60-2.72 (2H,m),2.72-2.81 (1H,m), 3.91 (3H,s), 4.35-4.42 (1H,brs), 7.04 (2H,d,J=6.8 Hz),7.13 (2H,d,J=6.8 Hz), 7.36 (1H,dd,J=3.2, 9.2 Hz), 7.61 (1H,d,J=9.2 Hz),7.63 (1H,d,J=3.2 Hz)

Example 2293-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2-ethyl-6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 5-amino-2-fluoroisonicotinic acid, propionic anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.23 (3H,t,J=7.2 Hz), 1.65-1.76 (2H,m),1.85-1.96 (4H,m), 2.03-2.15 (4H,m), 2.16-2.28 (2H,m), 2.46 (2H,q,J=7.2Hz) 2.62-2.72 (2H,m), 2.73-2.82 (1H,m), 4.38-4.44 (1H,m), 7.06(2H,d,J=8.8 Hz), 7.13 (2H,d,J=6.8 Hz), 7.65 (1H,d,J=3.2 Hz), 8.81 (1H,s)

Example 2303-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was synthesized as a white solid (m.p.:161-163° C.)by the method according to Example 94, using5-amino-2-fluoroisonicotinic acid, acetic anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline as starting materials,followed by recrystallization (ethyl acetate/diethyl ether/n-heptane).

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.75 (2H,m), 1.80-1.93 (4H,m),2.00-2.11 (4H,m), 2.12-2.24 (2H,m), 2.28 (3H,s), 2.60-2.70 (2H,m),2.72-2.78 (1H,m), 4.36-4.42 (1H,m), 7.05 (2H,d,J=6.8 Hz), 7.13(2H,d,J=6.8 Hz), 7.65 (1H,d,J=4.0 Hz), 8.77 (1H,s)

Example 2313-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:190-192° C.)by the method according to Example 94, using 2-amino-6-fluorobenzoicacid, acetic anhydride and 4-[(1-cyclobutylpiperidin-4-yl)oxy]anilinemonotosylate as starting materials, followed by recrystallization (ethylacetate).

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.75 (2H,m), 1.83-1.93 (4H,m),2.00-2.11 (4H,m), 2.13-2.24 (2H,m), 2.24 (3H,s), 2.60-2.68 (2H,m),2.72-2.79 (1H,m), 4.36-4.41 (1H,m), 7.04 (2H,d,J=8.8 Hz), 7.08-7.14(3H,m), 7.46 (1H,d,J=8.0 Hz), 7.65-7.71 (1H,m)

Example 2323-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone

The title compound was synthesized as a light yellow solid(m.p.:122-125° C.) by the method according to Example 94, using2-amino-5-fluorobenzoic acid, acetic anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline monotosylate as startingmaterials, followed by recrystallization (ethyl acetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.63-1.75 (2H,m), 1.84-1.92 (4H,m),2.01-2.12 (4H,m), 2.16-2.24 (2H,m), 2.25 (3H,s), 2.61-2.70 (2H,m),2.72-2.81 (1H,m), 4.36-4.42 (1H,m), 7.04 (2H,d,J=8.8 Hz), 7.14(2H,d,J=8.8 Hz), 7.45-7.51 (1H,m), 7.68 (1H,dd,J=4.8, 8.8 Hz), 7.89(1H,dd,J=3.2, 8.0 Hz)

Example 2333-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:163-166° C.)by the method according to Example 94, using 2-amino-4-fluorobenzoicacid, acetic anhydride and 4-[(1-cyclobutylpiperidin-4-yl)oxy]anilinemonotosylate as starting materials, followed by recrystallization (ethylacetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.75 (2H,m), 1.82-1.96 (4H,m),2.00-2.11 (4H,m), 2.14-2.24 (2H,m), 2.25 (3H,s), 2.60-2.68 (2H,m),2.72-2.79 (1H,m), 4.36-4.41 (1H,m), 7.04 (2H,d,J=8.4 Hz), 7.12-7.20(3H,m), 7.31 (1H,dd,J=2.0, 9.6 Hz), 8.27 (1H,dd,J=6.0, 8.4 Hz)

Example 2343-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6,7-difluoro-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-4,5-difluorobenzoic acid, acetic anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline and monotosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.66-1.75 (2H,m), 1.83-1.95 (4H,m),2.00-2.11 (4H,m), 2.16-2.24 (2H,m), 2.24 (3H,s), 2.60-2.68 (2H,m),2.72-2.79 (1H,m), 4.35-4.42 (1H,m), 7.04 (2H,d,J=8.4 Hz), 7.13(2H,d,J=8.4 Hz), 7.44 (1H,dd,J=6.8, 10.4 Hz), 8.01 (1H,dd,J=8.4, 9.6 Hz)

Example 2353-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2-ethyl-5-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-methyl benzoic acid, propionic anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline monotosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.20 (3H,t,J=7.0 Hz), 1.69 (2H,m), 1.88(4H,m), 2.05 (4H,m), 2.19 (2H,m), 2.44 (2H,q,J=7.0 Hz), 2.63 (2H,m),2.75 (1H,m), 2.82 (3H,s), 4.37 (1H,m), 7.04 (2H,d,J=8.4 Hz), 7.13(2H,d,J=8.4 Hz), 7.21 (1H,d,J=7.2 Hz), 7.54 (1H,d,J=8.0 Hz), 7.59 (1H,dd, J=7.2, 8.0 Hz)

Example 2363-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2-ethyl-5-fluoro-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-fluorobenzoic acid, propionic anhydride and4-[(1-cyclobutylpiperidine 4-yl)oxy]aniline monotosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.20 (3H,t,J=7.2 Hz), 1.64-1.76 (2H,m),1.83-1.96 (4H,m), 2.00-2.10 (4H,m), 2.14-2.23 (2H,m), 2.44 (2H,q,J=7.2Hz) 2.60-2.68 (2H,m), 2.71-2.79 (1H, m), 4.35-4.40 (1H,m), 7.04(2H,d,J=8.8 Hz), 7.06-7.08 (1H,m), 7.12 (2H,d,J=8.8 Hz), 7.49(1H,d,J=8.0 Hz), 7.64-7.70 (1H,m)

Example 2373-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2-ethyl-5-methoxy-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-methoxybenzoic acid, propionic anhydride and4-[(1-cyclobutylpiperidine 4-yl)oxy]aniline monotosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.20 (3H,t,J=7.2 Hz), 1.64-1.76 (2H,m),1.83-1.96 (4H,m), 2.00-2.10 (4H,m), 2.14-2.22 (2H,m), 2.43 (2H,q,J=7.2Hz) 2.60-2.68 (2H,m), 2.71-2.79 (1H,m), 3.95 (3H,s), 4.35-4.40 (1H,m),6.86 (1H,d,J=8.0 Hz), 7.01 (2H,d,J=8.8 Hz), 7.10 (2H,d,J=8.8 Hz), 7.28(1H,d,J=8.0 Hz), 7.64 (1H, t, J=8.0 Hz)

Example 2385-chloro-3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2-ethyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-chlorobenzoic acid, propionic anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline monotosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.20 (3H,t,J=7.2 Hz), 1.62-1.78 (2H,m),1.83-1.96 (4H,m), 2.00-2.10 (4H,m), 2.14-2.22 (2H,m), 2.44 (2H,q,J=7.2Hz), 2.60-2.68 (2H,m), 2.71-2.79 (1H,m), 4.35-4.40 (1H,m), 7.03(2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.45 (1H,dd,J=2.8, 6.4 Hz),7.57-7.62 (2H,m)

Example 2393-{3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone(1) Manufacture of 3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]anilinemonotosylate

3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline was obtainedaccording to the method of Example 94, using 2-bromo-4-nitrophenol,N-Boc-4-piperidinol and cyclobutanone as starting materials. By treatingthis with 1 Eq of p-toluenesulfonic acid monohydrate, the targetcompound was obtained as a colorless solid. 2-bromo-4-nitrophenol wasmanufactured by the method described in the literature (J. Org. Chem.,Vol. 62, 1997, p. 4504).

(2) Manufacture of3-{3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-fluorobenzoic acid, acetic anhydride and3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.67-1.75 (2H,m), 1.86-2.10 (8H,m), 2.26(3H,s), 2.28-2.38 (2H,m), 2.52-2.63 (2H,m), 2.74-2.83 (1H,m), 4.50-4.54(1H,m), 7.03 (1H,d, J=8.8 Hz), 7.08-7.15 (2H,m), 7.45-7.47 (2H,m),7.72-7.66 (1H,m)

Example 2403-{3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino-6-methylbenzoic acid, acetic anhydride and3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.72 (2H,m), 1.80-2.15 (8H,m), 2.24 (3H,s),2.34 (2H,m), 2.44 (2H,m), 2.78 (1H,m), 2.81 (3H,s), 4.52 (1H,brs), 7.04(1H,d,J=8.8 Hz), 7.14 (1H,dd,J=2.4, 8.8 Hz), 7.23 (1H,d,J=7.8 Hz), 7.46(1H,d,J=2.4 Hz), 7.50 (1H,d,J=7.8 Hz), 7.60 (1H,t,J=7.8 Hz)

Example 2413-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2-ethyl-5-(trifluoromethyl)-4(3H)-quinazolinonehydrochloride

The title compound was obtained by the method according to Example 94,using 2-amino-6-(trifluoromethyl)benzoic acid, propionic anhydride,4-[(1-cyclobutylpiperidin-4-yl) oxy] aniline and monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.32 (3H,t,J=6.8 Hz), 1.75-1.83 (1H,m),1.98-2.07 (1H,m), 2.17-2.29 (4H,m), 2.72-2.91 (8H,m), 3.35-3.43 (3H,m),4.78-4.81 (1H,m), 7.08 (2H,d,J=8.0 Hz), 7.24 (2H,d,J=8.4 Hz), 7.92-8.00(2H,m), 8.40 (1H,d,J=7.8 Hz)

Example 2423-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone

The title compound was synthesized as a light brown solid (m.p.:177-179°C.) by the method according to Example 94, using 2-amino-4-fluorobenzoicacid, acetic anhydride and 4-[(1-cyclobutylpiperidin-4-yl)oxy]anilinemonotosylate as starting materials, followed by recrystallization (ethylacetate/diethyl ether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.66-1.75 (2H,m), 1.84-1.95 (4H,m),2.02-2.11 (4H,m), 2.17-2.28 (2H,m), 2.31 (3H,s), 2.61-2.68 (2H,m),2.75-2.80 (1H,m), 4.37-4.43 (1H,m), 7.05 (2H,d,J=9.3 Hz), 7.14(2H,d,J=9.3 Hz), 7.42-7.37 (1H,m), 7.47-7.52 (1H,m), 8.05 (1H,d,J=7.8Hz)

Example 2432-[3-(benzyloxy)propyl]-3-{4-[(1-cyclopentylpiperidin-4-yl)oxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one(1) Manufacture of 2-{[4-(benzyloxy)butanoyl]amino}nicotinic acid

4-(benzyloxy)butyric acid (154 mg, 0.79 mmol) was dissolved inchloroform, thionyl chloride (158 mg) was added, and the mixture stirredat room temperature for 1 Hour. The solvent and excess thionyl chloridewere distilled off under reduced pressure, the residue was dissolved inchloroform, triethylamine (0.46 mL) and 2-aminonicotinic acid ethylester (110 mg, 0.66 mmol) were added, and the mixture stirred at roomtemperature for 2 hours. Saturated sodium hydrogen carbonate aqueoussolution was added to the reaction liquid, the mixture extracted withchloroform, and dried with anhydrous sodium sulfate. The obtainedresidue was dissolved in methanol, 2N sodium hydroxide aqueous solution(0.66 mL) was added, and the mixture stirred at room temperature for 2hours. After adding hydrochloric acid aqueous solution to the reactionliquid to render it weakly acid, the solvent was distilled off underreduced pressure. Ethyl acetate and a small amount of ethanol were addedto the residue, the solid precipitate was filtered off, and the targetcompound (166 mg, 80%) was thus obtained as a colorless solid.

(2) Manufacture of2-[3-(benzyloxy)propyl]-4H-pyrido[2,3-d][1,3]oxadin-4-one

2-{[4-(benzyloxy)butanoyl]amino}nicotinic acid (100 mg, 0.32 mmol) wasdissolved in chloroform (4 mL) in a current of nitrogen, oxalyl chloride(50 microL) was added, and the mixture stirred at room temperature for 2hours. Triethylamine (0.2 mL) was added to the reaction liquid, andstirred for 1 Hour. Saturated sodium hydrogen carbonate aqueous solutionwas added, and the mixture extracted with chloroform. This was driedwith anhydrous sodium sulfate, concentrated, and the target compound (42mg, 45%) was thus obtained as a brown oily residue.

(3) Manufacture of2-[3-(benzyloxy)propyl]-3-{4-[(1-cyclopentylpiperidin-4-yl)oxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 2-[3-(benzyloxy)propyl]-4H-pyrido[2,3-d][1,3]oxazin-4-one and4-[(1-cyclopentylpiperidin-4-yl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.43-1.53 (2H,m), 1.53-1.62 (2H,m),1.68-1.76 (2H,m), 1.86-1.94 (4H,m), 2.03-2.12 (2H,m), 2.13-2.19 (2H,m),2.35-2.46 (2H,m), 2.55-2.61 (1H,m), 2.62 (2H,t,J=7.2 Hz), 2.82-2.88(2H,m), 3.54 (2H,t,J=5.6 Hz), 4.37-4.42 (1H,m), 4.40 (2H,s) 7.02(2H,d,J=8.8 Hz), 7.12 (2H,d,J=8.8 Hz), 7.17 (2H,d,J=8.0 Hz), 7.22-7.28(3H,m), 7.41 (1H,dd,J=4.8, 8.0 Hz), 8.58 (1H,dd,J=2.0, 8.0 Hz), 8.98(1H,dd,J=2.0, 4.4 Hz)

Example 2442-[2-(allyloxy)ethyl]-6-chloro-3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one(1) Manufacture of2-[2-(allyloxy)ethyl]-6-chloro-4H-pyrido[3,4-d][1,3]oxadin-4-one

The target compound was obtained by the method according to Example 243,using 5-amino-2-chloroisonicotinic acid ethyl ester and3-(allyloxy)propionic acid as starting materials.

(2) Manufacture of2-[2-(allyloxy)ethyl]-6-chloro-3-{4-[(1-cyclobutylpiperidin-yl)oxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 2-[2-(allyloxy)ethyl]-6-chloro-4H-pyrido[3,4-d][1,3]oxadin-4-oneand 4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.75 (2H,m), 1.83-1.94 (4H,m),2.00-2.11 (4H,m), 2.16-2.23 (2H,m), 2.60-2.69 (2H,m), 2.76 (2H,t,J=6.4Hz), 3.86 (2H,t,J=6.4 Hz), 3.97 (2H,dt,J=1.2, 6.0 Hz), 4.35-4.42 (1H,m),5.17 (2H,dd,J=1.2, 10.4 Hz), 5.22-5.28 (2H,m), 5.81-5.90 (1H,m), 7.03(2H,d,J=8.8 Hz), 7.10 (2H,d,J=8.8 Hz), 8.06 (1H,s), 8.91 (1H,s)

Example 2456-chloro-3-[4-[(1-cyclopropylpiperidin-4-yl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(1) Manufacture of 1-cyclopropyl-4-(4-nitrophenoxy)piperidine

4-(4-nitrophenoxy)piperidine (1.92 g, 8.63 mmol) and[(1-ethoxycyclopropyl)oxy](trimethyl)silane (2.27 g, 12.9 mmol) weredissolved in a mixed solvent of acetic acid (20 mL) and methanol (20mL), sodium cyanoborohydride (1.08 g, 17.3 mmol) was added, and themixture stirred at 65° C. for 18 hours. The solvent was distilled offunder reduced pressure, ethyl acetate and 1N sodium hydroxide aqueoussolution were added, the mixture was extracted with ethyl acetate, andthe organic phase was washed with distilled water. After drying withanhydrous sodium sulfate, the product was concentrated, and the targetcompound (1.94 g, 86%) was thus obtained as a light brown oilysubstance. 4-(4-nitrophenoxy)piperidine was that manufactured in Example94.

(2) Manufacture of 4-[(1-cyclopropyl piperidin-4-yl)oxy]aniline

The target compound was obtained by catalytic reduction of1-cyclopropyl-4-(4-nitrophenoxy)piperidine in a mixed solvent ofmethanol and ethyl acetate, using a palladium charcoal catalyst.

(3) Manufacture of6-chloro-3-{4-[(1-cyclopropylpiperidin-4-yl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 94,using 5-amino-2-chloroisonicotinic acid, acetic anhydride and4-[(1-cyclopropylpiperidin-4-yl) oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.41-0.50 (4H,m), 1.62-1.65 (1H,m),1.80-1.88 (2H,m), 1.97-2.04 (2H,m), 2.29 (3H,s), 2.48-2.57 (2H,m),2.90-2.96 (2H,m), 4.37-4.42 (1H,m), 7.06 (2H,d,J=8.8 Hz), 7.13(2H,d,J=8.8 Hz), 8.06 (1H,s), 8.90 (1H,s)

Example 2463-{4-[(1-cyclopropylpiperidin-4-yl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of6-chloro-3-{4-[(1-cyclopropyl-piperidin-4-yl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 251 using a palladium charcoal catalyst in thepresence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 0.41-0.50 (4H,m), 1.62-1.66 (1H,m),1.79-1.88 (2H,m), 1.97-2.04 (2H,m), 2.30 (3H, s), 2.49-2.56 (2H,m),2.90-2.96 (2H,m), 4.37-4.42 (1H,m), 7.06 (2H,d,J=8.8 Hz), 7.13(2H,d,J=8.8 Hz), 8.03 (1H,d,J=5.2 Hz), 8.68 (1H,d,J=5.2 Hz), 9.13 (1H,s)

Example 2473-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-(difluoromethoxy)-2-methyl-(3H)-quinazolinone(1) Manufacture of3-{4-[(1-cyclobutylpiperidin-yl)oxy]phenyl}-6-hydroxy-methyl-(3H)-quinazolinone

The target compound was obtained by demethylating 3-{4-1(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinonesynthesized in Example 234 by the method according to Example 192 (1).

(2) Maufacture of3-{4-[1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-(difluoromethoxy)-2-methyl-4(3H)-quinazolinone

3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-hydroxy-2-methyl-4(3H)-quinazolinone(37 mg), sodium chlorodifluoroacetate (17 mg) and potassium carbonate(25 mg) were mixed in dimethylformamide, and stirred at 120° C. for 2hours. Distilled water was added to the reaction liquid, the mixture wasextracted with chloroform, and dried with anhydrous sodium sulfate. Theproduct was purified by silica gel column chromatography(chloroform/methanol=15/1), and the title compound (19 mg, 46%) was thusobtained as a light yellow oily residue.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.65-1.77 (2H,m), 1.84-1.97 (4H,m),2.01-2.10 (4H,m), 2.17-2.27 (5H,m), 2.61-2.68 (2H,m), 2.74-2.81 (1H,m),4.42-4.36 (1H,m), 6.61 (1H,t,J=73.2 Hz), 7.04 (2H,d, J=9.3 Hz), 7.14(2H,d,J=8.8 Hz), 7.53 (1H,dd,J=9.0, 2.7 Hz), 7.69 (1H,d,J=8.8 Hz), 7.94(1H,d,J=2.9 Hz)

Example 2483-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-methoxy-2-methyl-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 94,using 2-amino 4-methoxybenzoic acid, acetic anhydride and4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.65-1.76 (2H,m), 1.83-1.95 (4H,m),2.00-2.09 (4H,m), 2.15-2.23 (2H,m), 2.24 (3H,s), 2.60-2.68 (2H,m),2.71-2.79 (1H,m), 3.93 (3H,s), 4.35-4.41 (1H,m), 7.06-7.01 (4H,m), 7.14(2H,d,J=9.3 Hz), 8.16 (1H,d,J=8.8 Hz

Example 2496-chloro-3-(2-methoxy-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1) Manufacture of6-chloro-3-(4-hydroxy-2-methoxyphenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 1-(1)and -(2), using 5-amino-2-chloroisonicotinic acid, acetic anhydride and4-amino-3-methoxyphenol as starting materials.

(2) Manufacture of6-chloro-3-(2-methoxy-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one6-chloro-3-(4-hydroxy-2-methoxyphenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(250 mg, 0.79 mmol, 3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol (186 mg,1.2 mmol) and triphenylphosphine (310 mg, 1.2 mmol)-were dissolved indry tetrahydrofuran (6 mL) in a current of nitrogen, and cooled on anice bath. Diisopropyl azodicarboxylate (0.23 mL, 1.2 mmol) was drippedin, and stirred for 2 days at room temperature. The mixture wasconcentrated under reduced pressure, diethyl ether was added, and thesolid precipitate was filtered off. The filtrate was concentrated, theproduct was purified by silica gel column chromatography(chloroform/methanol=100/0-95/5), and the title compound (200 mg, 56%)was thus obtained as colorless crystals.

¹HNMR (400 MHZ,CDCl₃,δppm): 0.83-0.93 (4H,m), 1.55-1.74 (5H,m),1.84-1.89 (1H,m), 1.99-2.06 (2H,m), 2.25 (3H,s), 2.50 (2H,t,J=7.3 Hz),2.83-2.91 (2H,m), 3.77 (3H,s), 4.07 (2H,t,J=6.3 Hz), 6.61-6.64 (2H,m),7.05-7.07 (1H,m), 8.05 (1H,s), 8.89 (1H,s)

Example 2506-chloro-3-(2-hydroxy-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

6-chloro-3-(2-methoxy-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 249 was demethoxylated by the method according toExample 192 (1), and the title compound was thus obtained.

¹HNMR (400 MHz,CDCl₃,δppm): 0.77-0.89 (4H,m), 1.52-1.74 (5H,m),1.97-2.07 (3H,m), 2.32 (3H,s), 2.64-2.81 (2H,m), 2.96-3.07 (2H,m), 3.97(2H,t,J=5.6 Hz), 6.41-6.39 (1H,m), 6.44 (1H,dd,J=8.8, 2.4 Hz), 6.98(1H,d,J=8.3 Hz), 8.04 (1H,s), 8.89 (1H,s)

Example 2516-chloro-3-(2-(2-fluoroethoxy)-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 192(1), using6-chloro-3-(2-hydroxy-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 250 and 2-fluoroethyl tosylate as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.83-0.93 (4H,m), 1.53-1.74 (5H,m),1.84-1.91 (1H,m), 1.99-2.06 (2H,m), 2.27 (3H,s), 2.51 (2H,t,J=7.3 Hz),2.83-2.92 (2H,m), 4.07 (2H,t,J=6.3 Hz), 4.10-4.34 (2H,m), 4.49-4.51(1H,m), 4.63-4.61 (1H,m), 6.64 (1H,d,J=2.4 Hz), 6.67 (1H,dd,J=8.8, 2.4Hz), 7.09 (1H,d,J=8.8 Hz), 8.05 (1H,s), 8.90 (1H,s)

Example 2522-ethyl-6-methoxy-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 249,using2-ethyl-6-methoxy-3-(4-hydroxyphenyl)pyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 198 and3-[(2S)-2-methylpyrrolidin-1-yl]propan-1-ol as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.11 (3H,d,J=6.0 Hz), 1.23 (3H,t,J=7.2 Hz),1.40-1.50 (1H,m), 1.60-2.37 (8H,m), 2.44 (2H,q,J=7.2 Hz), 2.97-3.03(1H,m), 3.18-3.23 (1H,m), 4.03 (3H,s), 4.07-4.11 (2H,m), 7.05(2H,d,J=9.2 Hz), 7.12 (2H,d,J=9.2 Hz), 7.45 (1H,s), 8.78 (1H,s)

Example 2532-ethyl-6-methoxy-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-(3H)-onehydrochloride

The title compound was obtained by the method according to Example 249,using2-ethyl-6-methoxy-3-(4-hydroxyphenyl)pyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 198 and3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.00 (3H,d,J=6.8 Hz), 1.07-1.13 (1H,m), 1.22(3H,t,J=7.6 Hz), 1.82-1.98 (6H,m), 2.40-2.54 (4H,m), 3.17-3.23 (2H,m),3.47-3.65 (2H,m), 4.03 (3H,s), 4.16 (2H,t,J=5.4 Hz), 7.02 (2H,d,J=8.8Hz), 7.15 (2H,d,J=8.8 Hz), 7.44 (1H,s), 8.79 (1H,s)

Example 2546-methoxy-3-(2-methoxy-4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-2-methylpyrido[3,4-d]pyrimidin-(3H)-one

The title compound was obtained by the method according to Example 249,using6-methoxy-3-(4-hydroxy-2-methoxyphenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 203 (1) and3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.82-0.93 (4H,m), 1.57-1.74 (5H,m),1.84-1.91 (1H,m), 1.99-2.06 (2H,m), 2.20 (3H,s), 2.52 (2H,t,J=7.3 Hz),2.85-2.92 (2H,m), 3.76 (3H,s), 4.02 (3H,s), 4.07 (2H,t,J=6.3 Hz),6.59-6.62 (2H,m), 7.07 (1H,d,J=8.8 Hz), 7.45 (1H,s), 8.75 (1H,s)

Example 2556-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 249,using3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 197 and3-[(3S)-3-methyl-piperidin-1-yl]propan-1-ol as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.86-0.91 (4H,m), 1.56-1.75 (5H,m),1.85-1.93 (1H,m), 2.00-2.08 (2H,m), 2.24 (3H,s), 2.50-2.56 (2H,m),2.85-2.95 (2H,m), 4.03 (3H,s), 4.07 (2H,t,J=6.0 Hz), 7.05 (2H,d,J=8.8Hz), 7.14 (2H,d,J=8.8 Hz), 7.45 (1H,s), 8.75 (1H,s)

Example 2566-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 249,using3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 197 and3-[(2R)-2-methylpyrrolidin-1-yl]propan-1-ol as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.17 (3H,d,J=4.9 Hz), 1.47-2.50 (12H,m),3.01-3.10 (1H,m), 3.23-3.31 (1H,m), 4.03 (3H,s), 4.12-4.08 (2H,m), 7.05(2H,d,J=8.8 Hz), 7.14 (2H,d,J=8.8 Hz), 7.45 (1H,s), 8.75 (1H,s)

Example 2572,5-dimethyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-6-methylbenzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.13 (3H,d,J=5.9 Hz), 1.42-1.51 (1H,m),1.61-2.09 (5H,m), 2.17-2.54 (6H,m), 2.82 (3H,s), 2.99-3.04 (1H,m),3.20-3.25 (1H,m), 4.05-4.11 (2H,m), 7.03-7.07 (2H,m), 7.13-7.16 (2H,m),7.21 (1H,d,J=7.3 Hz), 7.50 (1H,d,J=7.8 Hz), 7.59 (1H, t, J=7.8 Hz)

Example 2582-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-5-(trifluoromethyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-6-(trifluoromethyl)benzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.14 (3H,d,J=6.3 Hz), 1.42-1.51 (1H,m),1.61-1.86 (2H,m), 1.91-2.10 (3H,m), 2.15-2.43 (6H,m), 2.98-3.06 (1H,m),3.20-3.25 (1H,m), 4.04-4.11 (2H,m), 7.03-7.06 (2H,m), 7.14-7.18 (2H,m),7.80 (1H,t,J=7.8 Hz), 7.86-7.89 (2H,m)

Example 2595-chloro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-6-chlorobenzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.13 (3H,d,J=5.9 Hz), 1.41-1.51 (1H,m),1.59-2.08 (5H,m), 2.14-2.54 (6H,m), 2.99-3.04 (1H,m), 3.20-3.25 (1H,m),4.04-4.13 (2H,m), 7.03-7.06 (2H,m), 7.12-7.16 (2H,m), 7.45 (1H,dd,J=7.3,1.5 Hz), 7.55-7.62 (2H,m)

Example 2605-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was synthesized as a white solid (m.p.:125-127° C.)by the method according to Example 165, using 2-amino-6-fluorobenzoicacid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl)propoxy]aniline monotosylate asstarting materials, followed by recrystallization (ethyl acetate/diethylether).

¹HNMR (400 MHz,CDCl₃,δppm): 1.13 (3H,d,J=6.3 Hz), 1.41-1.51 (1H,m),1.60-1.85 (2H,m), 1.91-2.09 (3H,m), 2.14-2.54 (6H,m), 2.99-3.06 (1H,m),3.20-3.25 (1H,m), 4.05-4.13 (2H,m), 7.03-7.15 (6H,m), 7.46 (1H,d,J=8.3Hz), 7.65-7.70 (1H,m)

Example 2616-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-5-fluorobenzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz, CDCl₃,δppm): 1.13 (3H,d,J=5.9 Hz), 1.42-1.51 (1H,m),1.59-1.86 (2H,m), 1.91-2.09 (3H,m), 2.15-2.54 (6H,m), 2.99-3.06 (1H,m),3.20-3.25 (1H,m), 4.06-4.12 (2H,m), 7.04-7.07 (2H,m), 7.13-7.16 (2H,m),7.45-7.50 (1H,m), 7.66-7.69 (1H,m), 7.88-7.91 (1H,m)

Example 2627-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-4-fluorobenzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.15 (3H,d,J=5.9 Hz), 1.44-1.53 (1H,m),1.60-1.87 (2H,m), 1.92-2.11 (3H,m), 2.20-2.56 (6H,m), 3.01-3.08 (1H,m),3.23-3.27 (1H,m), 4.06-4.14 (2H,m), 7.04-7.07 (2H,m), 7.13-7.20 (3H,m),7.31 (1H,dd,J=9.3, 2.4 Hz), 8.27 (1H,dd,J=8.8, 6.3 Hz)

Example 2638-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-3-fluorobenzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.16 (3H,d,J=6.3 Hz), 1.44-1.54 (1H,m),1.62-1.85 (2H,m), 1.93-2.12 (3H,m), 2.21-2.41 (6H,m), 3.01-3.08 (1H,m),3.23-3.28 (1H,m), 4.06-4.14 (2H,m), 7.05-7.08 (2H,m), 1.13-7.17 (2H,m),7.37-7.42 (1H,m), 7.47-7.51 (1H,m), 8.05 (1H,d,J=7.8 Hz)

Example 2642,6-dimethyl-3-(4-[3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone

The title compound was obtained by the method according to Example 165,using 2-amino-5-methyl benzoic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.15 (3H,d,J=6.3 Hz), 1.47-1.53 (1H,m),1.62-1.84 (2H,m), 1.92-2.11 (3H,m), 2.20-2.54 (9H,m), 3.01-3.08 (1H,m),3.23-3.27 (1H,m), 4.06-4.12 (2H,m), 7.03-7.06 (2H,m), 7.13-7.16 (2H,m),7.57-7.57 (2H,m), 8.05 (1H,s)

Example 2652-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 2-aminonicotinic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.15 (3H,d,J=6.3 Hz), 1.44-1.53 (1H,m),1.63-1.87 (2H,m), 1.92-2.11 (3H,m), 2.18-2.40 (6H,m), 3.01-3.08 (1H,m),3.22-3.27 (1H,m), 4.06-4.14 (2H,m), 7.05-7.08 (2H,m), 7.14-7.17 (2H,m),7.40-7.43 (1H,m), 8.59 (1H,dd,J=7.8, 2.0 Hz), 8.98-8.99 (1H,m)

Example 2662-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one

The title compound was synthesized as a light yellow solid(m.p.:238-250° C.) by the method according to Example 165, using4-aminonicotinic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy]aniline monotosylate asstarting materials, followed by recrystallization (ethyl acetate/diethylether/n-heptane).

¹HNMR (400 MHz,CDCl₃,δppm): 1.14 (3H,d,J=6.3 Hz), 1.42-1.51 (1H,m),1.61-1.85 (2H,m), 1.91-2.10 (3H,m), 2.15-2.38 (6H,m), 3.00-3.07 (1H,m),3.21-3.25 (1H,m), 4.08-4.12 (2H,m), 7.05-7.09 (2H,m), 7.13-7.16 (2H,m),7.48-7.50 (1H,m), 8.85 (1H,d,J=5.9 Hz), 9.47 (1H,d,J=1.0 Hz)

Example 2672-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one(1) Manufacture of6-chloro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The target compound was obtained by the method according to Example 165,using 5-amino-2-chloroisonicotinic acid, acetic anhydride and4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline monotosylate asstarting materials.

(2) Manufacture of2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by dissolving6-chloro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,4-d]pyrimidin-4(3H)-onein ethyl acetate, and performing catalytic reduction with a palladiumcharcoal catalyst in the presence of triethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.11 (3H,d,J=5.9 Hz), 1.39-1.48 (1H,m),1.59-1.85 (2H,m), 1.89-2.08 (3H,m), 2.10-2.41 (6H,m), 2.97-3.04 (1H,m),3.17-3.22 (1H,m), 4.08-4.12 (2H,m), 7.06-7.09 (2H,m), 7.13-7.16 (2H,m),8.03 (1H,dd,J=5.4, 1.0 Hz), 8.67 (1H,d,J=5.4 Hz), 9.12 (1H,d,J=1.0 Hz)

Example 2682-methyl-3-[4-(3-piperidin-1-yl-propoxy)phenyl]pyrido[3,2-d]pyrimidin-4(3H)-one(1) Manufacture of 3-nitropyridine-2-carboxylic acid

This was manufactured by the method described in the literature(Tetrahedron, 1998, Vol. 54, p. 6311; and J. Am. Chem. Soc., 1954, Vol.76, p. 3167) using 2-chloro-3-nitropyridine as starting material.

(2) Manufacture of 3-aminopyridine-2-carboxylic acid

3-nitropyridine-2-carboxylic acid (2.72 g, 16.2 mmol) and sodiumhydrogencarbonate (1.34 g, 16.2 mmol) were dissolved in distilled water(20 mL), and the atmosphere in the system was replaced by nitrogen.After adding 10% palladium charcoal (1.72 g), the atmosphere in thesystem was replaced by hydrogen, and the mixture stirred at roomtemperature for 50 hours. 1N hydrochloric acid aqueous solution wasadded, and the pH of the reaction solution was adjusted to weak acidity.The solvent was distilled off under reduced pressure, a small amount ofethanol and ethyl acetate were added to the residue, and the precipitateproduced was filtered off. The filtrate was concentrated, and the targetsubstance (1.50 g, 67%) was thus obtained as a light yellow solid.

(3) Manufacture of3-[4-(3-piperidin-1-yl-propoxy)phenyl]-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 3-aminopyridine-2-carboxylic acid, acetic anhydride and4-(3-piperidin-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.49-1.43 (2H,m), 1.58-1.63 (4H,m), 2.02(2H,dt,J=14.6, 6.3 Hz), 2.27 (3H,s), 2.37-2.45 (4H,m), 2.50 (2H,t,J=7.6Hz), 4.07 (2H,t,J=6.3 Hz), 7.06 (2H,td,J=2.4, 9.3 Hz), 7.17(2H,td,J=2.4, 9.3 Hz), 7.68 (1H,dd,J=8.3, 4.4 Hz), 8.01 (1H,dd,J=8.3,1.5 Hz), 8.86 (1H,dd,J=4.4, 1.5 Hz)

Example 2692-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 3-aminopyridine-2-carboxylic acid synthesized in Example 268,acetic anhydride and 4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}anilinemonotosylate as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.13 (3H,d,J=5.9 Hz), 1.51-1.42 (1H,m),1.68-1.87 (2H,m), 1.93-2.00 (1H,m), 2.01-2.10 (2H,m), 2.16-2.30 (4H,m),2.27 (3H,s), 2.32-2.42 (1H,m), 3.03 (1H,dt,J=12.2, 7.8 Hz), 3.23(1H,td,J=8.3, 2.9 Hz), 4.09 (2H,td,J=5.9, 2.4 Hz), 7.06 (2H,d,J=8.8 Hz),7.17 (2H,d,J=8.8 Hz), 7.68 (1H,dd,J=8.3, 4.4 Hz), 8.01 (1H,dd,J=8.3, 1.5Hz), 8.86 (1H,dd,J=4.4, 1.5 Hz)

Example 2702-methyl-3-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]pyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 3-aminopyridine-2-carboxylic acid synthesized in Example 268,acetic anhydride and 4-(3-pyrrolidin-1-yl-propoxy)aniline as startingmaterials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.79-1.86 (4H,m), 2.03-2.10 (2H,m), 2.27(3H,s), 2.56-2.62 (4H,m), 2.69 (2H,t,J=7.3 Hz), 4.09 (2H,t,J=6.3 Hz),7.06 (2H,td,J=2.4, 8.8 Hz), 7.17 (2H,td,J=2.4, 8.8 Hz), 7.68(1H,dd,J=8.3, 4.4 Hz), 8.01 (1H,dd,J=8.3, 1.5 Hz), 8.85 (1H,dd,J=4.4,1.5 Hz)

Example 2712-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 3-amino pyridine-2-carboxylic acid synthesized in Example 268,acetic anhydride and 4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}anilinemonotosylate as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 0.94-0.82 (1H,m), 0.88 (3H,d,J=6.8 Hz),1.57-1.74 (5H,m), 1.89 (1H,td,J=11.2, 2.9 Hz), 2.04 (2H,q,J=6.3 Hz),2.27 (3H,s), 2.53 (2H,t,J=7.6 Hz), 2.86-2.93 (2H,m), 4.07 (2H,t,J=6.3Hz), 7.05 (2H,d,J=8.8 Hz), 7.17 (2H,d,J=8.8 Hz), 7.67 (1H,dd,J=8.3, 4.4Hz), 8.00 (1H,dd,J=8.3, 1.5 Hz), 8.84 (1H,dd,J=4.4, 1.5 Hz).

Example 2723-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]phenyl}-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 3-amino pyridine-2-carboxylic acid synthesized in Example 268,acetic anhydride and 4-[(1-cyclobutylpiperidin-4-yl)oxy]anilinemonotosylate as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.67-1.74 (2H,m), 1.96-1.84 (4H,m),2.03-2.10 (4H,m), 2.17-2.25 (2H,m), 2.27 (3H,s), 2.59-2.71 (2H,m),2.73-2.79 (1H,m), 4.36-4.42 (1H,m), 7.05 (2H,td,J=2.0, 8.8 Hz), 7.17(2H,td,J=2.0, 8.8 Hz), 7.67 (1H,dd,J=8.3, 4.4 Hz), 8.00 (1H,dd,J=8.3,1.5 Hz), 8.84 (1H,dd,J=4.4, 1.5 Hz)

Example 2733-{4-[(1-cyclobutyl-piperidin-4-yl)oxy]phenyl}-2-ethylpyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 165,using 3-aminopyridine-2-carboxylic acid synthesized in Example 268,propionic anhydride and 4-[(1-cyclobutylpiperidin-4-yl)oxy]anilinemonotosylate as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.22 (3H,t,J=7.3 Hz), 1.64-1.76 (2H,m),1.84-1.95 (4H,m), 2.00-2.10 (4H,m), 2.15-2.23 (2H,m), 2.46 (2H,q,J=7.3Hz), 2.60-2.69 (2H,m), 2.73-2.79 (1H,m), 4.34-4.42 (1H,m), 7.04(2H,d,J=8.8 Hz), 7.15 (2H,d,J=8.8 Hz), 7.67 (1H,dd,J=8.3, 4.4 Hz), 8.05(1H,dd,J=8.3, 1.5 Hz), 8.85 (1H,dd,J=4.4, 1.5 Hz)

Example 2743-[4-(3-azepan-1-yl-propoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(1) Manufacture of3-[4-(3-azepan-1-yl-propoxy)phenyl]-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The target compound was obtained by the method according to Example 165,using 5-amino-2-chloroisonicotinic acid, acetic anhydride and4-(3-azepan-1-yl-propoxy)aniline as starting materials.

(2) Manufacture of3-[4-(3-azepan-1-yl-propoxy)phenyl]-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by catalytic reduction of3-[4-(3-azepan-1-yl-propoxy)phenyl]-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onein ethyl acetate using a palladium charcoal catalyst in the presence oftriethylamine.

¹HNMR (400 MHz,CDCl₃,δppm): 1.64-1.73 (8H,m), 2.08-2.10 (2H,m), 2.30(3H,s), 2.77-2.79 (6H,m), 4.11 (2H,t,J=6.1 Hz), 7.07 (2H,d,J=9.5 Hz),7.15 (2H,d,J=11.7 Hz), 8.03 (1H,dd,J=5.4, 1.0 Hz), 8.68 (1H,d,J=4.9 Hz),9.13 (1H,s).

Example 2753-[4-(3-azepan-1-yl-propoxy)phenyl]-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was obtained by the method according to Example 249,using3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-onesynthesized in Example 268 and 3-(azepan-1-yl)propan-1-ol as startingmaterials.

¹HNMR (400 MHZ,CDCl₃,δppm): 1.63-1.69 (8H,m), 2.01-2.04 (2H,m), 2.24(3H,s), 2.71-2.74 (6H,m), 4.03 (3H,s), 4.09 (2H,t,J=6.1 Hz), 7.05(2H,d,J=8.8 Hz), 7.14 (2H,d,J=6.6 Hz), 7.45 (1H,d,J=1.0 Hz), 8.76 (1H,s)

Example 2763-[4-(3-azepan-1-yl-propoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The target compound was obtained by the method according to Example 165,using 2-aminonicotinic acid, acetic anhydride and4-(3-azepan-1-yl-propoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.62-1.65 (8H,m), 1.95-2.02 (2H,m), 2.35(3H,s), 2.65-2.69 (6H,m), 4.09 (2H,t,J=6.3 Hz), 7.07 (2H,d,J=11.7 Hz),7.15 (2H,d,J=12.2 Hz), 7.42 (1H,dd,J=7.8, 4.9 Hz), 8.59 (1H,dd,J=7.8,2.0 Hz), 8.99 (1H,q,J=2.3 Hz)

Example 2775-fluoro-2-methyl-3-[4-(3-pyrrolidin-1-ylbutoxy)phenyl]-4(3H)-quinazolinone(racemic mixture) (1) Manufacture of 4-(3-pyrrolidin-1-yl-butoxy)aniline(Racemic Mixture)

The target compound was obtained by the method according to Example 18,using 3-pyrrolidin-1-yl-butan-1-ol (racemic mixture) manufactured by themethod described in the literature (J. Org. Chem., 1949, Vol. 14, p.862) and 4-nitrofluorobenzene as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.14 (3H,d, J=6.3 Hz), 1.82-1.65 (5H,m),2.10 (1H,m), 2.61-2.53 (5H,m), 3.41 (1H,brs), 3.97 (2H,m), 6.64(2H,d,J=9.0 Hz), 6.75 (2H,d,J=9.0 Hz)

(2) Manufacture of5-fluoro-2-methyl-3-[4-(3-pyrrolidin-1-yl-butoxy)phenyl]-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by the method according to Example 18,using 2-amino-6-fluorobenzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl-butoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.17 (3H,d,J=6.8 Hz), 1.79 (4H,m), 1.88(1H,m), 2.15 (1H,m), 2.24 (3H,s), 2.61 (5H,m), 4.10 (2H,m), 7.05(2H,d,J=9.0 Hz), 7.08 (1H,m), 7.14 (2H,d,J=9.0 Hz), 7.46 (1H,d,J=8.3Hz), 7.68 (1H,m)

Example 2782-methyl-3-[4-(3-pyrrolidin-1-yl-butoxy)phenyl]-5-(trifluoromethyl)-4(3H)-quinazolinone(Racemic Mixture)

The title compound was obtained by the method according to Example 18,using 2-amino-6-(trifluoromethyl)benzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl-butoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.17 (3H,d,J=6.8 Hz), 1.80 (4H,m), 1.88(1H,m), 2.15 (1H,m), 2.27 (3H,s), 4.09 (2H,m), 2.62 (5H,m), 7.05(2H,d,J=9.0 Hz), 7.16 (2H,d, J=9.0 Hz), 7.80 (1H,t,J=7.8 Hz), 7.87(1H,d,J=7.8 Hz), 7.88 (1H,d,J=7.8 Hz)

Example 2792,5-dimethyl-3-[4-(3-pyrrolidin-1-yl-butoxy)phenyl]-4(3H)-quinazolinone(Racemic Mixutre)

The title compound was obtained by the method according to Example 18,using 2-amino-6-methylbenzoic acid, acetic anhydride and4-(3-pyrrolidin-1-yl-butoxy)aniline as starting materials.

¹HNMR (400 MHz,CDCl₃,δppm): 1.17 (3H,d,J=6.3 Hz), 1.80 (4H,m), 1.88(1H,m), 2.15 (1H,m), 2.22 (3H,s), 2.62 (5H,m), 2.82 (3H,s), 4.09 (2H,m),7.05 (2H,d,J=8.8 Hz), 7.15 (2H,d,J=8.8 Hz), 7.21 (1H,d,J=7.6 Hz), 7.50(1H,d,J=7.6 Hz), 7.59 (1H,t,J=7.6 Hz)

Pharmacological test examples, in which2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone (thecompound of Exaple 1) was used as a test compound, are shown below.

Pharmacological Test Example 1: Histamine Analog Coupling InhibitionTest

A cDNA sequence [International Patent Application WO00/3916Specification No. 4] which encodes human histamine H3 receptor wascloned using the expression vectors pCR2.1, pEF1x (product ofInvitrogen), and pCI-neo (product of Promega Inc.). The expressionvector obtained was transfected to the host cells, HEK293 and CHO-K1(American type culture collection), using the cationic lipid method[Proceedings of the National Academy of Sciences of the United States ofAmerica, Vol. 84, p. 7413 (1987), and histamine H3 receptor expressioncells were thus obtained.

A film preparation made from the cells which represented the histamineH3 receptor, the test compound (the compound of Exaple 1) and 20,000 cpmof [3H]N-α-methylhistamine (product of NEN) were incubated in an assaybuffer solution (50 mM Tris buffer solution, pH 7.4) at 25° C. for 2hours, and filtered on a glass filter GF/C. After washing by 50 mM Trisbuffer solution, pH7.4, the radioactivity on the glass filter was found.Non-specific linkages were measured in the presence of 10 microMthioperamide (product of SIGAM), and the 50% inhibition concentration(IC₅₀ value) of the test compound with respect to specificN-α-methylhistamine linkages was found (Molecular Pharmacology, Vol. 55,p. 1101 (1999)). As a result, the IC₅₀ value of the test compound was 15nM.

As described above, the compound of Exaple 1 strongly prevented bindingof N-α-methylhistamine to the histamine H3 receptor (histamine analog).

Pharmacological Test Example 2: Antagonism Test of Drinking BehaviorInduced by R-α-Methylhistamine, a Histamine H3 Receptor SelectiveAgonist

Under ketamine/xylazine anaesthesia (74 mg/kg and 11 mg/kgintraperitoneal single-dose administration), a chronic guide cannula (26gauge, length 11 mm) was inserted in the ventriculus tertius of a maleSD rat (7-10 weeks old, 200-300 g) using a brain stereotaxis apparatus,and fixed by dental resin. The position of the tip of the guide cannulawas 2.2 mm back from the bregma, and at a depth of 8 mm from the skullsurface on the median line. After about 1 week convalescence,R-α-methylhistamine (0.3 μg/1 μL/head, 30% propylene glycol solution)was administered to the ventriculus tertius. The test compound (thecompound of Exaple 1) suspended in 0.5% methylcellulose aqueous solutionwas administered orally 2 hours before the R-α-methylhistamineadministration, and the drinking water amount was measured 1 hour afterR-α-methylhistamine administration. As a result, the test compound (10mg/kg) significantly suppressed the increase in drinking water amountdue to R-α-methylhistamine administered to the ventriculus tertius.

Pharmacological Test Example 3: In Vitro Kinetic Test

The test compound (the compound of Exaple 1) was administered orally orintravenously to SD type male rats (7-10 weeks old, 200-400 g) which hadabstained from food overnight, and about 100 μL of blood was collectedfrom a caudal vein using a heparinized capillary tube at a predeterminedtime. The blood was centrifuged (4° C., 6000 rpm, 10 minutes), andplasma was obtained. Three times the amount of ethanol (containing aninternal reference) was added to the plasma, stirred, left for 20minutes at −20° C., and centrifuged (4° C., 10,000 rpm, 10 minutes). Thesupernatant liquid was analyzed by LC/MS/MS, and the plasmaconcentration was measured by the relative calibration curve method. Asa result, the test compound had 60% bioavailability, and a half-life of6.3 hours in blood.

Pharmacological Test Example 4: Brain/Cerebrospinal Fluid Activity Test

The test compound (the compound of Exaple 1) was administered orally orintravenously to SD type male rats (7-10 weeks old, 200-400 g), andexsanguination was performed from the abdominal aorta under etheranesthesia using a heparin treatment syringe at a predetermined time.The skin at the back of the head was cut open, pierced with a 30G dentalneedle between the cervical vertebrae, and inserted into thesubarachnoid space. 50-100 μL of cerebrospinal fluid was extracted by a1 mL syringe via a tube connected to the 30G needle, and the brain wasextracted. A blood sample was centrifuged (4° C., 6000 rpm, 10 minutes),and three times the amount of ethanol (containing an internal reference)was added to the plasma and stirred. 2 mL of water was added to a brainsample, homogenized, a part was removed, and three times the amount ofethanol (containing an internal reference) was added and stirred. Thecerebrospinal fluid was taken, three times the amount of ethanol(containing an internal reference) was added, and stirred. The abovesample was left at −20° C. for 0.20 minutes, centrifuged (4° C., 12,000g, 10 minutes), the supernatant liquid was analyzed by LC/MS/MS, and theconcentration in plasma, brain and cerebrospinal fluid was measured bythe relative calibration curve method. As a result, the test compoundhad an intracerebral concentration of 3.16 nmol/g, cerebrospinal fluidconcentration of 0.142 μM, and plasma concentration of 2.32 μM at 2hours after oral administration (10 mg/kg).

The novel fused ring 4-oxopyrimidine derivative represented by formula(I), or a pharmaceutically acceptable salt thereof, has a powerfulhistamine antagonistic or inverse agonistic activity, and is thereforeuseful in the prophylaxis or therapy of metabolic diseases such asobesity, diabetes mellitus, hormone secretion disorders, hyperlipidemia,gout and fatty liver; circulatory diseases such as angina pectoris,acute or congestive heart failure, myocardial infarction, annulararteriosclerosis, hypertension, kidney disease and electrolyteimbalance; or central or peripheral nervous system diseases such assleep disorders or diseases accompanied by sleep disorders (e.g.,idiopathic hypersomnia, repeatability hypersomnia, intrinsichypersomnia, narcolepsy, periodic limb movement during sleep, sleepapnea syndrome, circadian rhythm hindrance, chronic fatigue syndrome,REM sleep hindrance, sleep loss in the elderly, night shift worker sleepinsanitation, idiopathic insomnia, repeatability insomnia, intrinsicinsomnia, depression, insecurity and schizophrenia), bulimia, emotionaldisorders, epilepsy, delirium, dementia, attention deficit/hyperactivitydisorder, memory impairment, Alzheimer's disease, Parkinson's disease,cognitive disorder, movement disorder, dysesthesia, dysosmia, morphineresistance, narcotics dependence, alcohol dependence and tremor.

1. A compound represented by formula (I):

[where Ar is a divalent group formed by eliminating two hydrogen atomsfrom benzene, pyrimidine, pyridine, thiazole, oxazole, pyrazole,thiadiazole or thiophene (this divalent group may be further substitutedby a halogen atom, lower alkoxy (this lower alkoxy group may be furthersubstituted by halogen), hydroxy or lower alkyl); X¹ is a nitrogen atom,sulfur atom or oxygen atom; R¹ is a 5- or 6-membered heteroaryl grouphaving 1 to 4 heteroatoms selected from among nitrogen, sulfur andoxygen, heteroarylalkyl group (heteroaryl in this group has the samemeaning as the above), straight chain or branched lower alkyl (thislower alkyl group may be further substituted by hydroxy, halogen,alkoxy, allyloxy or aralkyloxy), phenyl, aralkyl, alkoxy, alkylthio orlower alkylamino; Ring A is a 5- or 6-membered heteroaryl ring having 1or 2 nitrogen atoms or sulfur atoms in the ring, or a benzene ring; R²and R³ may be the same or different, and each represents hydrogen,amino, alkylamino, dialkylamino, nitro, cyano, hydroxy, loweralkylsulfonyl, halogen, lower alkyl (this lower alkyl group may befurther substituted by halogen), lower cycloalkyl (this lower cycloalkylgroup may be further substituted by halogen), lower alkoxy (this loweralkoxy group may be further substituted by halogen or hydroxy), lowercycloalkoxy (this lower cycloalkoxy group may be further substituted byhalogen), aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, aryl,heteroaryl, arylcarbamoyl, heteroarylcarbamoyl, arylalkylcarbamoyl,heteroarylalkylcarbamoyl, mono-lower alkylcarbamoyl, di-loweralkylcarbamoyl, lower alkylcarboxamide, arylcarboxamide,heteroarylcarboxamide, arylalkylcarboxamide, heteroarylalkylcarboxamide,alkanoyl, arylcarbonyl, arylalkylcarbonyl, formyl, hydroxy, alkylthio,alkoxycarbonylamino, lower alkylsulfonylamino, arylsulfonylamino,alkylaminosulfonyl, arylaminosulfonyl, aralkyl, alkanoylamino oralkanoylalkylamino; Y is CH or a nitrogen atom; —X² is a grouprepresented by formula (II):

(where R⁴ and R⁵ may be the same or different, and each is a lower alkylgroup (this lower alkyl group may be further substituted by halogen) ora cycloalkyl group, or R⁴, R⁵ and a nitrogen atom together form a 5- to8-membered monocyclic ring (this monocyclic ring may be substituted by ahalogen atom, an oxo group, or a lower alkyl group which itself may besubstituted by halogen), or a 6- to 10-membered bicyclo ring, n is aninteger of 2 to 4, and (CH₂)_(n) may be substituted by a lower alkylgroup having 1 to 3 carbon atoms), formula (III):

(where m is an integer from 0 to 4, and R⁶ is a lower alkyl orcycloalkyl group), or formula (IV):

(where the symbols have the same meaning as the above), with the provisothat formula (I) excludes3-[4-(2-diethylaminoethoxy)-phenyl]-2-methyl-3H-quinazolin-4-one,3-[4-(2-dimethylaminoethoxy)-phenyl]-2-methyl-3H-quinazolin-4-one,2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3H-quinazolin-4-one,3-[4-(3-dimethylaminopropoxy)-phenyl]-2-methyl-3H-quinazolin-4-one,3-[4-(3-diethylaminopropoxy)-phenyl]-2-methyl-3H-quinazolin-4-one and3-[2-(2-diethylaminoethoxy)-phenyl]-2-methyl-3H-quinazolin-4-one], or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein Ring A is a benzene ring, pyridine ring or pyrimidinering, or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1, wherein Ring A is a benzene ring or a pyridinering, or a pharmaceutically acceptable salt thereof.
 4. The compoundaccording to claim 1, wherein at least one of R² and R³ is a hydrogenatom, or a pharmaceutically acceptable salt thereof.
 5. The compoundaccording to claim 1, wherein one of R² and R³ is a hydrogen atom, andthe other is a hydrogen atom, a halogen atom, hydroxy, lower alkyl (thislower alkyl group may be further substituted by halogen), lower alkoxy(this lower alkoxy group may be further substituted by halogen orhydroxy), aryl (this aryl group may be further substituted by loweralkyl), heteroaryl, lower alkylcarboxamide, arylcarboxamide,arylalkylcarboxamide or lower alkylsulfonylamino, or a pharmaceuticallyacceptable salt thereof.
 6. The compound according to claim 1, whereinone of R² and R³ is a hydrogen atom, and the other is a hydrogen atom, ahalogen atom, lower alkyl (this lower alkyl group may be furthersubstituted by halogen), or lower alkoxy (this lower alkoxy group may befurther substituted by halogen), or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 1, wherein Ar is a divalentgroup formed by eliminating two hydrogen atoms from benzene orpyrimidine (this divalent group may be further substituted by a halogenatom, lower alkoxy (this lower alkoxy group may be further substitutedby halogen), hydroxy or lower alkyl), and n is 3 or 4, or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1, wherein —X² is represented by formula (II):

[where symbols have the same meaning as the above], or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 8, wherein n is 3 or 4, and R⁴, R⁵ and a nitrogen atom togetherform a 5- to 8-membered monocyclic ring (this monocyclic ring may haveas a substituent group a halogen atom, or a lower alkyl group which maybe substituted by halogen), or a pharmaceutically acceptable saltthereof.
 10. The compound according to claim 8, wherein n is 3 or 4, andR⁴, R⁵ and a nitrogen atom together form a 6- to 10-membered bicycloring, or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 8, wherein n is 3, and R⁴, R⁵ and a nitrogen atomtogether form a 5- to 8-membered monocyclic ring (this monocyclic ringmay have as a substituent group a halogen atom, or a lower alkyl groupwhich may be substituted by halogen), or a pharmaceutically acceptablesalt thereof.
 12. The compound according to claim 8, wherein n is 3, andR⁴, R⁵ and a nitrogen atom together form a 6- to 10-membered bicycloring, or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 1, wherein —X² is represented by formula (III):

[where symbols have the same meaning as the above], or apharmaceutically acceptable salt thereof.
 14. The compound according toclaim 1, wherein —X² is represented by formula (IV):

[where symbols have the same meaning as the above], or apharmaceutically acceptable salt thereof.
 15. The compound according toclaim 1, wherein R¹ is a lower alkyl group having 1 to 3 carbon atoms(this lower alkyl group may be further substituted by halogen), or aphenyl group, or a pharmaceutically acceptable salt thereof.
 16. Thecompound according to claim 1, wherein R¹ is methyl, ethyl, n-propyl,isopropyl or trifluoromethyl, or a pharmaceutically acceptable saltthereof.
 17. The compound according to claim 1, wherein the compoundrepresented by formula (I) is:2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(diethylamino)propoxy]phenyl}-2-methyl-4-(3H)-quinazolinone,2-methyl-3-{4-[3-(2-methyl-1-pyrrolidinyl)-propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(2,5-dimethyl-1-pyrrolidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,2-methyl-3-{4-[4-(1-piperidinyl)butoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(1-azepanyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[3-(1-azocanyl)propoxy]-phenyl}-2-methyl 4(3H)-quinazolinone,2-methyl-3-{4-[3-(2-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(4-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-(4-[3-[(2R,6S)-2,6-dimethyl-1-piperidinyl]propoxy}phenyl)-2-methyl-4(3H)-quinazolinone,2-methyl-3-{4-[3-(3-methyl-1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(3,5-dimethyl-1-piperidinyl)propoxy]phenyl}-2-methyl-4(3H)-quinazolinone,2-methyl-3-{3-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{3-bromo-4-[3-(1-piperidinyl)propoxy]phenyl}-2-ethyl-4(3H)-quinazolinone,2-methyl-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-4(3H)-quinazolinone,2,5-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,3-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-propyl-4(3H)-quinazolinone,3-{4-[3-(1-piperidinyl)propoxy]phenyl}-2-trifluoromethyl-4(3H)-quinazolinone,2-isopropyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2,6-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2,8-dimethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-ethyl-5-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-hydroxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinonetrifluoroacetate,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,7-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6,7-difluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-bromo-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6,7-dimethoxy-2-methyl-3-{4-[3-(1-piperidinyl)proproxy]phenyl}-4(3H)-quinazolinone,8-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,8-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2,6-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-ethyl-5-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4 (3H)-quinazolinone,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[2,3-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,6-chloro-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,2-methyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone,2,5-dimethyl-3-{2-[3-(1-piperidinyl)propoxy]-5-pyrimidinyl}-4(3H)-quinazolinone,2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[2,3-d]pyrimidin-4(3H)-one,6-chloro-2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,6-chloro-2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[3,4-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-pyrido[4,3-d]pyrimidin-4(3H)-one,6-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido-[3,4-d]pyrimidin-4(3H)-one, 3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(hexanoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-[(2-phenylacetyl)amino]2-methyl-3-(4-[3-(1-piperidinyl)propoxy]phenyl)-4(3H)-quinazolinone,6-(2-naphthoylamino)-2-methyl-3-(4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-[(methylsulfonyl)amino]-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-[(methylsulfonyl)amino]-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(acetylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(butyrylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(hexanoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(benzoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-[(2-phenylacetyl)amino]2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,7-(2-naphthoylamino)-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone6-[acetyl(methyl)amino]2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-(4-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-(3-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-6-(2-methylphenyl)-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(3-pyridyl)-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(4-pyridyl)-4(3H)-quinazolinone,2-methyl-5-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-6-(2-pyridyl)-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-cyclohexyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-isopropyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-ethyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-(1-butyl-4-piperidinyloxy)phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,3-{4-(1-cyclopentyl-4-piperidinyloxy)phenyl}-2,5-dimethyl-4(3H)-quinazolinone,7-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2,6-dimethyl-4(3H)-quinazolinone,6-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,6-chloro-3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido{3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,5-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,6-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,6-chloro-3-{4-[(1-cyclobutyl-4-piperidinyl)oxy-]phenyl}-2-ethylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,2-phenyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,cis-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone,trans-2-methyl-3-(4-{[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-3-pyrrolidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone3-{4-[(1-cyclopentyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-azepanyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone,3-methyl-2-{4-[3-(1-piperidinyl)propoxy]phenyl}-1(2H)-isoquinolinone,2-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-3-methyl-1(2H)-isoquinolinone,2-methyl-3-[4-{[3-(1-pyrrolidinyl)-cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone,2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one, or a pharmaceutically acceptable saltthereof.
 19. The compound according to claim 1, wherein the compoundrepresented by formula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 20. The compoundaccording to claim 1, wherein the compound represented by formula (I) is2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1, wherein the compound represented by formula (I) is2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 22. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone, or a pharmaceutically acceptable salt thereof. 23.The compound according to claim 1, wherein the compound represented byformula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 24. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 25. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 26. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 27. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 28. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 29. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 30. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 31. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 32. The compoundaccording to claim 1, wherein the compound represented by formula (I) is3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 33. The compoundaccording to claim 1, wherein the compound represented by formula (I) is6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 34. The compoundaccording to claim 1, wherein the compound represented by formula (I) is6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 35. The compoundaccording to claim 1, wherein the compound represented by formula (I) is2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 36. The compoundaccording to claim 1, wherein the compound represented by formula (I) is2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 37. The compoundaccording to claim 1, wherein the compound represented by formula (I) is5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 38. The compoundaccording to claim 1, wherein the compound represented by formula (I) is6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 39. The compoundaccording to claim 1, wherein the compound represented by formula (I) is5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 40. The compoundaccording to claim 1, wherein the compound represented by formula (I) is7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 41. The compoundaccording to claim 1, wherein the compound represented by formula (I) is2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 42. The compoundaccording to claim 1, wherein the compound represented by formula (I) is5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 43. The compoundaccording to claim 1, wherein the compound represented by formula (I) is2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 44. The compoundaccording to claim 1, wherein the compound represented by formula (I) is6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 45. The compoundaccording to claim 1, wherein the compound represented by formula (I) is6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,or a pharmaceutically acceptable salt thereof.
 46. A histamine H3receptor antagonist consisting of the compound according to claim
 1. 47.A histamine H3 receptor inverse agonist consisting of the compoundaccording to claim
 1. 48. A prophylactic or therapeutic agent for ametabolic disease, a circulatory disease or a nervous system diseasecontaining as an active ingredient the compound according to claim 1, ora pharmaceutically acceptable salt thereof.
 49. The prophylactic ortherapeutic agent according to claim 48, wherein the metabolic diseaseis at least one disease selected from the group consisting of obesity,diabetes mellitus, hormone secretion disorders, hyperlipidemia, gout andfatty liver.
 50. The prophylactic or therapeutic agent according toclaim 48, wherein the circulatory disease is at least one diseaseselected from the group consisting of angina pectoris, acute orcongestive heart failure, myocardial infarction, annulararteriosclerosis, hypertension, kidney disease and electrolyteimbalance.
 51. The prophylactic or therapeutic agent according to claim48, wherein the nervous system disease is at least one selected from thegroup consisting of sleep disorder, disease accompanied by sleepdisorder, bulimia, emotional disorder, epilepsy, delirium, dementia,attention deficit/hyperactivity disorder, memory impairment, Alzheimer'sdisease, Parkinson's disease, cognitive disorder, movement disorder,dysesthesia, dysosmia, morphine resistance, narcotics dependence,alcohol dependence and tremor.
 52. The prophylactic or therapeutic agentaccording to claim 48, wherein the nervous system disease is at leastone selected from the group consisting of idiopathic hypersomnia,repeatability hypersomnia, intrinsic hypersomnia, narcolepsy, periodiclimb movement during sleep, sleep apnea syndrome, circadian rhythmhindrance, chronic fatigue syndrome, REM sleep hindrance, sleep loss inthe elderly, night shift worker sleep insanitation, idiopathic insomnia,repeatability insomnia, intrinsic insomnia, depression, insecurity,schizophrenia.
 53. A prophylactic or therapeutic agent for a metabolicdisease, a circulatory disease or a nervous system disease containing asactive ingredients the compound according to claim 1, or apharmaceutically acceptable salt thereof, and a concomitant drug. 54.The prophylactic or therapeutic agent according to claim 53, wherein theconcomitant drug is anti-diabetic agents.
 55. The prophylactic ortherapeutic agent according to claim 53, wherein the concomitant drug islipid lowering agents.
 56. The prophylactic or therapeutic agentaccording to claim 53, wherein the concomitant drug is anti-hypertensiveagents.
 57. The prophylactic or therapeutic agent according to claim 53,wherein the concomitant drug is anti-obesity agents.
 58. A prophylacticor therapeutic agent for a metabolic disease, a circulatory disease or anervous system disease comprising the following (i) to (iii). (i) thecompound according to claim 1, or a pharmaceutically acceptable saltthereof; (ii) one or more compound(s) selected from the group consistingof the following (a) to (g): (a) Histamine H3 antagonist or inverseagonist other than (i), (b) a biguanide, (c) a PPAR agonist, (d)insulin, (e) somatostatin, (f) an α-glucosidase inhibitor, and (g)insulin secretagogues; and (iii) a pharmaceutically acceptable carrier.